How a Common Bacterium Can Trigger and Worsen Your Asthma

Introduction

Hello and welcome to the World Asthma Foundation blog, where we share the latest news and information on asthma and related topics. We are a non-profit organization that pursues our mission and vision with a strategy to support the asthma community with educational resources. Our goal is to foster improved outcomes, better doctor-patient relationships, and support joint decision-making. In this way, asthmatics can take charge of their own health.

One of our main areas of focus is Infectious Asthma, which is a term that describes asthma that is triggered or worsened by infections, such as bacteria, viruses, fungi or parasites. Infectious Asthma can affect anyone, but it is more common and severe in children, elderly, immunocompromised or low-income populations. Infectious Asthma can cause more frequent and severe asthma attacks, lung damage, chronic sinusitis, nasal polyps and other complications.

In this article, we will review the current knowledge on one of the most common and potentially harmful triggers of Infectious Asthma: Staphylococcus aureus (S. aureus), a bacterium that can colonize the skin and mucous membranes of humans. S. aureus can produce various toxins, such as staphylococcal enterotoxins (SE), that can act as superantigens and induce an intense immune response in the airways. This can result in increased production of immunoglobulin E (IgE), a type of antibody that mediates allergic reactions, and activation of eosinophils, a type of white blood cell that causes inflammation and tissue damage.

We will also discuss how measuring SE specific IgE (SE-IgE) may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions. Finally, we will provide some key takeaways and recommendations for asthmatics and clinicians.

We hope that this article will be informative and helpful for you. If you have any questions or comments, please feel free to contact us. Thank you for reading.

Summary

In this article, we have reviewed the current knowledge on the role of S. aureus and its enterotoxins in asthma, especially severe asthma. We have summarized the main findings from five recent studies that have investigated the association between SE sensitization and asthma severity, phenotype and inflammation. We have also discussed how measuring SE-IgE may help to phenotype asthmatics and guide treatment decisions. We have provided some key takeaways and recommendations for asthmatics and clinicians. Here are the main points:

•  S. aureus and its enterotoxins are important factors in the pathogenesis of asthma, especially severe asthma.

•  SE can act as superantigens and induce an intense T cell activation causing local production of polyclonal IgE and resultant eosinophil activation.

•  SE can also manipulate the airway mucosal immunology at various levels via other proteins, such as serine-protease-like proteins (Spls) or protein A (SpA), and trigger the release of IL-33, type 2 cytokines, mast cell mediators and eosinophil extracellular traps.

•  SE sensitization is associated with increased risk of asthma, more asthma exacerbations, nasal polyps, chronic sinusitis, lower lung function and more intense type-2 inflammation.

•  SE sensitization is also linked to allergic poly-sensitization and allergic multimorbidity, such as rhinitis, eczema and food allergy, indicating a possible role of S. aureus in the development of allergic diseases.

•  Measuring SE-IgE may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions, such as anti-IgE therapy or antibiotics.

Key Takeaways

•  Asthmatics should be aware of the potential role of S. aureus and its enterotoxins in triggering and worsening their asthma symptoms and seek medical advice if they suspect an infection or colonization.

•  Asthmatics should avoid contact with S. aureus carriers or sources of contamination, such as contaminated food or water, and practice good hygiene and wound care to prevent infection or colonization.

•  Asthmatics should ask their doctors about testing for SE-IgE as part of their asthma phenotyping and management, as it may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions.

•  Clinicians should consider measuring SE-IgE in asthmatics, especially those with severe asthma, nasal polyps, chronic sinusitis or allergic multimorbidity, as it may provide valuable information on the underlying mechanisms and phenotypes of asthma and suggest novel therapeutic targets and strategies.

•  Clinicians should also monitor the SE-IgE levels and response to treatment in asthmatics who are receiving anti-IgE therapy or antibiotics, as it may help to evaluate the efficacy and safety of these interventions.

Conclusion

Asthma is a complex and heterogeneous disease that can be influenced by various factors, such as allergens, irritants, infections and stress. Among these factors, S. aureus and its enterotoxins have emerged as important triggers and modulators of asthma, especially severe asthma. SE can act as superantigens and induce an intense immune response in the airways, resulting in increased production of IgE and activation of eosinophils. SE can also manipulate the airway mucosal immunology at various levels via other proteins, such as Spls or SpA, and trigger the release of IL-33, type 2 cytokines, mast cell mediators and eosinophil extracellular traps. These mechanisms can lead to more severe asthma phenotype and type-2 inflammation.

SE sensitization is associated with increased risk of asthma, more asthma exacerbations, nasal polyps, chronic sinusitis, lower lung function and more intense type-2 inflammation. SE sensitization is also linked to allergic poly-sensitization and allergic multimorbidity, such as rhinitis, eczema and food allergy, indicating a possible role of S. aureus in the development of allergic diseases. Measuring SE-IgE may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions, such as anti-IgE therapy or antibiotics.

In this article, we have reviewed the current knowledge on the role of S. aureus and its enterotoxins in asthma, especially severe asthma. We have summarized the main findings from five recent studies that have investigated the association between SE sensitization and asthma severity, phenotype and inflammation. We have also discussed how measuring SE-IgE may help to phenotype asthmatics and guide treatment decisions. We have provided some key takeaways and recommendations for asthmatics and clinicians.

We hope that this article has been informative and helpful for you. If you have any questions or comments, please feel free to contact us. Thank you for reading.

References

: Bachert C., Humbert M., Hanania N.A., Zhang N., Holgate S., Buhl R., Bröker B.M. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge. Eur Respir J. 2020;55(4):1901592. doi: 10.1183/13993003.01592-2019.

: Kanemitsu Y., Taniguchi M., Nagano H., Matsumoto T., Kobayashi Y., Itoh H. Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma. J Allergy Clin Immunol. 2012;130(2):376–382.e3. doi: 10.1016/j.jaci.2012.04.027.

: Soh J.Y., Lee B.W., Goh A. Staphylococcal enterotoxin specific IgE and asthma: a systematic review and meta-analysis. Pediatr Allergy Immunol. 2013;24(3):270–279.e1-4. doi: 10.1111/pai.12056.

: Schleich F., Brusselle G.G., Louis R., Vandenplas O., Michils A., Van den Brande P., Lefebvre W.A., Pilette C., Gangl M., Cataldo D.D., et al. Asthmatics only sensitized to Staphylococcus aureus enterotoxins have more exacerbations, airflow limitation, and higher levels of sputum IL-5 and IgE. J Allergy Clin Immunol Pract. 2023;11(5):1658–1666.e4. doi: 10.1016/j.jaip.2023.01.021.

: James A., Gyllfors P., Henriksson E.L., Lundahl J., Nilsson G., Alving K., Nordvall L.S., van Hage M., Cardell L.O. Staphylococcus aureus enterotoxin sensitization is associated with allergic poly-sensitization and allergic multimorbidity in adolescents. Clin Exp Allergy. 2015;45(6):1099–1107. doi: 10.1111/cea.12519.

Sidebar: What is Staphylococcus aureus?

Staphylococcus aureus is a type of bacteria that can cause various infections in humans and animals. It is found in the environment and also in the normal flora of the skin and mucous membranes of most healthy individuals. It can colonize the anterior nares (the front part of the nose), the throat, the skin, and the gastrointestinal tract. It is estimated that up to half of all adults are colonized by S. aureus, and approximately 15% of them persistently carry it in their noses.

S. aureus can cause infections when it breaches the skin or mucosal barriers and enters the bloodstream or internal tissues. These infections can range from mild skin infections, such as boils or impetigo, to more serious infections, such as pneumonia, endocarditis, osteomyelitis, septic arthritis, or sepsis. S. aureus can also produce toxins that can cause food poisoning, toxic shock syndrome, or scalded skin syndrome.

S. aureus is a very adaptable and versatile bacterium that can acquire resistance to various antibiotics. The most notorious example is methicillin-resistant S. aureus (MRSA), which is resistant to most beta-lactam antibiotics, such as penicillins and cephalosporins. MRSA can cause infections both in community-acquired and hospital-acquired settings and poses a major public health challenge.

S. aureus is believed to have originated in Central Europe in the mid-19th century and has since evolved and diversified into many different strains or clones. Some of these strains are more virulent or resistant than others and have spread globally through human migration and travel. One of these strains is ST8, which includes the USA300 clone that is responsible for most community-acquired MRSA infections in the United States.

S. aureus is one of the most common and potentially harmful triggers of Infectious Asthma, especially severe asthma. It can produce various toxins, such as staphylococcal enterotoxins (SE), that can act as superantigens and induce an intense immune response in the airways. This can result in increased production of immunoglobulin E (IgE), a type of antibody that mediates allergic reactions, and activation of eosinophils, a type of white blood cell that causes inflammation and tissue damage.

References

: Staphylococcus aureus Infection – StatPearls – NCBI Bookshelf

: Global Epidemiology and Evolutionary History of Staphylococcus aureus ST45

: Origin, evolution, and global transmission of community-acquired … – PNAS

: Staphylococcus aureus Infections: Epidemiology, Pathophysiology 

The World Asthma Foundation Announces Speakers for Microbiome First Summit

On this World Asthma Day, May 3, 2002, The Microbiome First – Pathway to Sustainable Healthcare Summit organization committee invites healthcare professionals, non-communicable disease community leaders, and stakeholders to participate in the inaugural Microbiome First Summit, a virtual event taking place online at MicrobiomeFirst.org this May, 17-19, 2022. FREE to participants.

For detailed information and to register, visit: https://microbiomefirst.org/

The event, Microbiome First – Pathway to Sustainable Healthcare Summit, kicks off the inaugural event underwritten and moderated by the
World Asthma Foundation (WAF), which is pleased to announce the
following speakers:

Event Keynote
RODNEY DIETERT, PHD
Cornell University Professor Emeritus
Ithaca, NY, USA
Author of The Human Superorganism.
Keynote: “Big Picture View of Our Tiny Microbes”

Researcher Sessions
MARIE-CLAIRE ARRIETA, PHD
Associate Professor, departments of Physiology, Pharmacology, and Pediatrics, University of Calgary
Calgary AB, CANADA
Session: “The early-life mycobiome in immune and metabolic development”

JAEYUN SUNG, PHD
Assistant Professor, Microbiome Program, Center for Individualized Medicine, Mayo Clinic.
Rochester, MN, USA
Session: “A predictive index for health status using species-level gut microbiome profiling”

KATRINE L. WHITESON, PHD
Assistant Professor, Molecular Biology and Biochemistry School of Biological Sciences
Associate Director, UCI Microbiome Initiative
Irvine, CA, USA
Session: “High-Fiber, Whole-Food Dietary Intervention Alters the Human Gut Microbiome but Not Fecal Short-Chain Fatty Acids”

LISA AZIZ-ZADEH, PHD
Cognitive neuroscientist; Expert in brain imaging, autism, body cognition
Associate Professor in the USC Chan Division of Occupational Science and Occupational Therapy
Los Angeles, CA, USA
Session: “Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder”

MARTIN KRIEGEL, MD, PHD
Chief of Rheumatology and Clinical Immunology at University Hospital of Münster
GERMANY
Associate Professor Adjunct of Immunobiology at Yale School of Medicine.
Session: “Dietary Resistant Starch Effects on Gut Pathobiont Translocation and Systemic Autoimmunity”

ERICA & JUSTIN SONNENBURG, PHD
Senior research scientist and Associate Professor in the Department of Microbiology and Immunology at the Stanford University School of Medicine.
Palo Alto, CA, USA
Session: “Gut-microbiota-targeted diets modulate human immune status”

EMMA HAMILTON-WILLIAMS, PHD
Associate Professor
Principal Research Fellow
The University of Queensland Diamantina Institute
Faculty of Medicine
The University of Queensland
Translational Research Institute
Woolloongabba, QLD, AUSTRALIA
Session: “Metabolite-based Dietary Supplementation in Human Type 1 Diabetes is associated with Microbiota and Immune modulation”

ANDRES CUBILLOS-RUIZ, PHD
Scientist, Wyss Institute of Harvard University and Institute of Medical Engineering and Science at Massachusetts Institute of Technology
Cambridge, MA, USA
Session: “Protecting the Gut Microbiota from Antibiotics with Engineered Live Biotherapeutics”

EMERAN A MAYER, MD
Gastroenterologist, Neuroscientist, Distinguished Research Professor
Department of Medicine, UCLA David Geffen School of Medicine
Executive Director, G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA
Founding Director, UCLA Brain Gut Microbiome Center.
Los Angeles, CA, USA
Session: “The Gut–Brain Axis and the Microbiome: Mechanisms and Clinical Implications”

BENOIT CHASSAING, PHD
Principal Investigator, Chassaing Lab
Associate professor, French National Institute of Health and Medical Research.
Paris, FRANCE
Session: “Ubiquitous food additive and microbiota and intestinal environment”

SEI WON LEE, MD, PHD
Associate Professor
College of Medicine, University of Ulsan
Department of Pulmonary and Critical Care, Asan Medical Center
Seoul, KOREA
Session: “The Therapeutic Application of Gut-Lung Axis in Chronic Respiratory Disease”

PATRICIA MACCHIAVERNI, PHD
Clinical and translational researcher
Research Fellow, The University of Western Australia
Perth, WA, AUSTRALIA
Honorary Research Associate, Telethon Kids Institute.
Session:House Dust Mite Shedding in Human Milk: a Neglected Cause of Allergy Susceptibility?”

LIEKE VAN DEN ELSEN, PHD
Research Fellow, The University of Western Australia, Australia
Honorary Research Associate, Telethon Kids Institute.
Perth, WA, AUSTRALIA
Session: “Gut Microbiota by Breastfeeding: The Gateway to Allergy Prevention”

PAUL TURNER, PHD
Rachel Carson Professor of Ecology and Evolutionary Biology, Yale University
Microbiology faculty member, Yale School of Medicine.
New Haven, CT, USA
Session: “New Yale Center to Advance Phage Research, Understanding, Treatments, Training, Education”

ANDRES CUBILLOS- RUIZ, PHD
Scientist, Wyss Institute of Harvard University and Institute of Medical Engineering and Science of Massachusetts Institute of Technology MIT
Boston, MA, USA
Session: “Protecting the Gut Microbiota from Antibiotics with Engineered Live Biotherapeutics”

CLAUDIA S. MILLER, MD, MS
Emeritus Professor, Allergy/Immunology and Environmental Health University of Texas San Antonio, TX, USA
Session: “Toxicant-Induced Lost of Tolerance for Chemicals, Foods and Drugs: a Global Phenomenon”

Media Supporter Content
TONI HARTMAN
PRINCIPAL
Microbiome Courses
London, England UK
Session “Educating Parents About ‘Seeding And Feeding’ A Baby’s Microbiome”

Summit Details:

The goal of the Microbiome First – Sustainable Healthcare Summit is to
improve quality of life at reduced cost by addressing the microbiome
first, as recent research shows that all of these non-communicable diseases have a relationship to the microbiome.

For additional information visit https://microbiomefirst.org/ or on Twitter at @MicrobiomeFirst https://twitter.com/MicrobiomeFirst

Bisphenol A or BPA in Pregnancy and Asthma Study

The Barcelona Institute for Global Health supported study concludes suggests that in utero BPA exposure may be associated with higher odds of asthma and wheeze among school-age girls.

Study Background

In utero, (before birth) exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only.

Study Objectives

There is growing concern over the role of chemical pollutants on early life origins of respiratory diseases (Gascon et al., 2013, Vrijheid et al., 2016, Casas and Gascon, 2020, Abellan and Casas, 2021), specifically on bisphenols due to their large production worldwide (CHEMTrust, 2018) and its widespread exposure to human populations (Calafat et al., 2008, Haug et al., 2018). Bisphenol A (BPA) is the most commonly used bisphenol. It is present in polycarbonate plastics and epoxy resins, used in many consumer products, and diet is the main source of exposure (Liao and Kannan, 2013). In 2017, the European Chemical Agency considered BPA as a “substance of very high concern” (Calafat et al., 2008, Agency and Bisfenol, 2017). Consequently, BPA production is restricted in some countries, which has resulted in the emergence of substitutes such as bisphenol F (BPF) and bisphenol S (BPS), with suspected similar toxicity (Lehmler et al., 2018, Rochester and Bolden, 2015). Bisphenols can cross the placenta and are also found in breastmilk, which results in exposure to foetuses and newborns (Lee et al., 2018). To examine the associations of in utero exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex.

Methods

We included 3,007 mother–child pairs from eight European birth cohorts. Bisphenol concentrations were determined in maternal urine samples collected during pregnancy (1999–2010). Between 7 and 11 years of age, current asthma and wheeze were assessed from questionnaires and lung function by spirometry. Wheezing patterns were constructed from questionnaires from early to mid-childhood. We performed adjusted random-effects meta-analysis on individual participant data.

In utero exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only.

Study Objective

To examine the associations of in utero exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex.

Results

Exposure to BPA was prevalent with 90% of maternal samples containing concentrations above detection limits. BPF and BPS were found in 27% and 49% of samples. In utero exposure to BPA was associated with higher odds of current asthma (OR = 1.13, 95% CI = 1.01, 1.27) and wheeze (OR = 1.14, 95% CI = 1.01, 1.30) (p-interaction sex = 0.01) among girls, but not with wheezing patterns nor lung function neither in overall nor among boys. We observed inconsistent associations of BPF and BPS with the respiratory outcomes assessed in overall and sex-stratified analyses.

Conclusion

This study suggests that in utero BPA exposure may be associated with higher odds of asthma and wheeze among school-age girl

According the U.S. National Institute of Health, Bisphenol A (BPA) is a chemical produced in large quantities for use primarily in the production of polycarbonate plastics. It is found in various products including shatterproof windows, eyewear, water bottles, and epoxy resins that coat some metal food cans, bottle tops, and water supply pipes.

How does BPA get into the body?

The primary source of exposure to BPA for most people is through the diet. While air, dust, and water are other possible sources of exposure, BPA in food and beverages accounts for the majority of daily human exposure.

Bisphenol A can leach into food from the protective internal epoxy resin coatings of canned foods and from consumer products such as polycarbonate tableware, food storage containers, water bottles, and baby bottles. The degree to which BPA leaches from polycarbonate bottles into liquid may depend more on the temperature of the liquid or bottle, than the age of the container. BPA can also be found in breast milk.

Why are people concerned about BPA?
One reason people may be concerned about BPA is because human exposure to BPA is widespread. The 2003-2004 National Health and Nutrition Examination Survey (NHANES III) conducted by the Centers for Disease Control and Prevention (CDC) found detectable levels of BPA in 93% of 2517 urine samples from people six years and older. The CDC NHANES data are considered representative of exposures in the United States. Another reason for concern, especially for parents, may be because some animal studies report effects in fetuses and newborns exposed to BPA.

If I am concerned, what can I do to prevent exposure to BPA?

Some animal studies suggest that infants and children may be the most vulnerable to the effects of BPA. Parents and caregivers can make the personal choice to reduce exposures of their infants and children to BPA:

  • Don’t microwave polycarbonate plastic food containers. Polycarbonate is strong and durable, but over time it may break down from over use at high temperatures.
    Plastic containers have recycle codes on the bottom. Some, but not all, plastics that are marked with recycle codes 3 or 7 may be made with BPA.
  • Reduce your use of canned foods.
    When possible, opt for glass, porcelain or stainless steel containers, particularly for hot food or liquids.
  • Use baby bottles that are BPA free.

There is growing concern over the role of chemical pollutants on early life origins of respiratory diseases (Gascon et al., 2013, Vrijheid et al., 2016, Casas and Gascon, 2020, Abellan and Casas, 2021), specifically on bisphenols due to their large production worldwide (CHEMTrust, 2018) and its widespread exposure to human populations (Calafat et al., 2008, Haug et al., 2018). Bisphenol A (BPA) is the most commonly used bisphenol. It is present in polycarbonate plastics and epoxy resins, used in many consumer products, and diet is the main source of exposure (Liao and Kannan, 2013). In 2017, the European Chemical Agency considered BPA as a “substance of very high concern” (Calafat et al., 2008, Agency and Bisfenol, 2017). Consequently, BPA production is restricted in some countries, which has resulted in the emergence of substitutes such as bisphenol F (BPF) and bisphenol S (BPS), with suspected similar toxicity (Lehmler et al., 2018, Rochester and Bolden, 2015). Bisphenols can cross the placenta and are also found in breastmilk, which results in exposure to foetuses and newborns (Lee et al., 2018).

Can we test for whats in the Microbiome? – Justin L. Sonnenburg PhD

Defeating Asthma Series uncovers New Hope for Asthma Management

In this interview with Justin L. Sonnenburg PhD, Associate Professor of Microbiology and Immunology at Stanford University, we learn about:

* Testing for Microbes within the Microbiome

* That we’re in the early stages of our understanding of the Microbiome

* Research that still needs to be done

Our understanding of Asthma and the way we treat it may soon be radically different from what currently exists, due to new research on the human microbiome and how the microbiome affects asthma.

“Diseases largely driven by inflammation and an altered immune system. If we start to take our gut microbiota into account, as we live our life, as we make medical decisions, eat different foods and potentially even eventually reintroduce some of these lost microbes, how profound can the impact be on our health?” Justin L. Sonnenburg Ph.D

Interview

World Asthma Foundation:  Dr. Sonnenburg, can we test for what’s in the microbiome?

Video Interview Can we test for whats in the Microbiome? – Justin L. Sonnenburg PhD

Dr. Justin L. Sonnenburg: On an individual level, there are companies that offer testing for the different species to give you the composition of what’s in your microbiome. I can’t speak to the validity of any of these companies, but there are commercial entities out there that will provide a profile for individuals.

World Asthma Foundation:  Thanks. Do you know if it’s specific? For example, research reflects that Bifidobacterium breve and Lactobacillus specifically have been targeted. I’m not a hundred percent sure if it’s inflammation or infection or both, it seems to be successful. The question is, can we test for those specific bacteria?

Dr. Justin L. Sonnenburg: There are targeted tests out there for specific bacteria that where we think given the species may be of interest. Of course, this is most famous for infectious agents. If you want to go in and see if you have Clostridium difficile or salmonella or something like that, there are specific targeted tests. These are less common for the good guys in our gut. I think part of the reason is we still don’t have a great understanding of what the good guys are.

There are studies out there that indicate certain associated with health States are associated with being able to fight off specific problems.

In general, quite often what’s found for one population when surveyed in an independent population doesn’t necessarily hold up.

There’s just extreme variability in the gut microbiome. I think as much as we know about the field is still how fundamental this community is to our health, we’re still at a really early stage of understanding what is healthy and also coming to grips with the fact that there is no single definition of healthy, that healthy really depends on the individual, the context, and many other factors.

World Asthma Foundation: It’s a complex issue and relatively emerging, right?

Dr. Justin L. Sonnenburg:  Exactly. A lot of research still needs to be done.

World Asthma Foundation: Thank you everything that you do on a daily basis for the gut microbiome, certainly for your teachings and your writings and for your time today. Appreciate it.

Dr. Justin L. Sonnenburg: Wonderful being with you. Thanks so much.

Missing Microbes and Asthma Link Say Multiple Studies – Martin J Blaser MD

Defeating Asthma Series uncovers New Hope for Asthma Management

In this third interview with Martin J Blaser MD, Director of the Center for Advanced Biotechnology and Medicine at Rutgers Biomedical and Health Sciences and the Henry Rutgers Chair of the Human Microbiome and Professor of Medicine and Microbiology at the Rutgers Robert Wood Johnson Medical School in New Jersey and the Author of the “Missing Microbes – How the Overuse of Antibiotics is Fueling Our Modern Plagues.” we learn:

  • About the H. pylori and Asthma connection
  • Additional reserach looking into the connection between H. pylori and Asthma
  • Whether the Microbes can reintroduced
Video: Missing Microbes and Asthma Link Say Multiple Studies – Martin J Blaser MD

Asthma Foundation: Dr. Blaser, we’ve talked about the asthma connection and the H. pylori topic. Can you identify these missing microbes also with tests? 

Dr. Blaser: Yes. The paper with Jakob Stokholm in Nature Communications looked at this– We saw that there was a difference in the microbiome in the kids that were one year old. That was the age at which their microbiome made a difference, whether they’d have a risk of asthma or not. Then we asked, “Okay, what’s the difference in the specific microbes at age one between the positives and the negatives?” We identified about 20 microbes that were significantly different, mostly lost, mostly missing.

What was interesting is that a group from British Columbia, led by Dr. Brett Finlay and colleagues had published about this also. They had found, I think, four or five organisms and we matched on four of the five. Again, two independent studies finding the same relationship makes it stronger

World Asthma Foundation: If I understand correctly, your research is determining whether or not you can repopulate the H. pylori. Is that independent of the intestinal microbes? 

Dr. Blaser: In theory, yes. What’s interesting is that people have been interested in microbes and asthma for quite some time, and most of the concentration was in the large intestine, in the colon. We were interested in the stomach first, but then we got more involved in the colon also. I think that both compartments in the body are important. Both of them are important. They’re both subject to this terrible pressure of the disappearance of microbes because of such things as antibiotics and cesarean sections and the like. They’re both. All of these microbes are potentially replaceable. That’s the hope.

World Asthma Foundation: Fantastic, that’s the hope.

 

Asthma and Indoor Air Pollution:

Key insights for Asthmatics:

  • Makes Asthma Worse
  • Significant Association with Exacerbations
  • Among this panel of relatively moderate to severe asthmatics, the respiratory irritants produced by several domestic combustion sources were associated with increased morbidity.
  • Although there is abundant clinical evidence of asthmatic responses to indoor aeroallergens, the symptomatic impacts of other common indoor air pollutants from gas stoves, fireplaces, and environmental tobacco smoke have been less well characterized. These combustion sources produce a complex mixture of pollutants, many of which are respiratory irritants.
  • Results of an analysis of associations between indoor pollution and several outcomes of respiratory morbidity in a population of adult asthmatics residing in the U.S. Denver, Colorado, metropolitan area. A panel of 164 asthmatics recorded in a daily diary the occurrence of several respiratory symptoms, nocturnal asthma, medication use, and restrictions in activity, as well as the use of gas stoves, wood stoves, or fireplaces, and exposure to environmental tobacco smoke.
  • Multiple logistic regression analysis suggests that the indoor sources of combustion have a statistically significant association with exacerbations of asthma. For example, after correcting for repeated measures and autocorrelation, the reported use of a gas stove was associated with moderate or worse shortness of breath (OR, 1.60; 95% CI, 1.11-2.32), moderate or worse cough (OR, 1.71; 95% CI, 0.97-3.01), nocturnal asthma (OR, 1.01; 95% CI, 0.91-1.13), and restrictions in activity (OR, 1.47; 95% CI, 1.0-2.16
  • The WAF Editorial Board wishes to thank and acknowledge B D Ostro 1 , M J Lipsett, J K Mann, M B Wiener, J Selner
    California Environmental Protection Agency, Berkeley for their contribution to Asthma education and research.

Why Cell Biology of Asthma Matters

Cell types responsible for the major pathology in asthma:
1. Epithelial cells – initiate airway inflammation mucus, and
2. Smooth muscle cells – contract excessively to cause airway narrowing.

The clinical manifestations of asthma are caused by obstruction of the conducting airways of the lung. Two airway cell types are critical for asthma pathogenesis: epithelial cells and smooth muscle cells. Airway epithelial cells, which are the first line of defense against inhaled pathogens and particles, initiate airway inflammation and produce mucus, an important contributor to airway obstruction. The other main cause of airway obstruction is contraction of airway smooth muscle. Complementary experimental approaches involving cultured cells, animal models, and human clinical studies have provided many insights into diverse mechanisms that contribute to airway epithelial and smooth muscle cell pathology in this complex disease. Continued attention to the study of the cell biology of asthma will be crucial for generating new ideas for asthma prevention and treatment based on normalizing epithelial and smooth muscle function.

Note from the WAF editorial board: We wish to acknowledge and thank David J. Erle and Dean Sheppard, Lung Biology Center and Department of Medicine, University of California, San Francisco for their support for Asthma research and education.

Asthma is a common disease that affects up to 8% of children in the United States (Moorman et al., 2007) and is a major cause of morbidity worldwide. The principal clinical manifestations of asthma are repeated episodes of shortness of breath and wheezing that are at least partially reversible, recurrent cough, and excess airway mucus production. Because asthma involves an integrated response in the conducting airways of the lung to known or unknown triggers, it is a multicellular disease, involving abnormal responses of many different cell types in the lung (Locksley, 2010). Here we focus on the two cell types that are ultimately responsible for the major symptomatic pathology in asthma—epithelial cells that initiate airway inflammation in asthma and are the source of excess airway mucus, and smooth muscle cells that contract excessively to cause symptomatic airway narrowing. The current thinking about cell–cell communications that drive asthma (Fig. 1) is that known and unknown inhaled stimuli (i.e., proteases and other constituents of inhaled allergens, respiratory viruses, and air pollutants) stimulate airway epithelial cells to secrete the cytokines TSLP, interleukin (IL)-25, and IL-33, which act on subepithelial dendritic cells, mast cells, and innate lymphoid cells (iLCs) to recruit both innate and adaptive hematopoietic cells and initiate the release of T helper 2 (Th2) cytokines (principally IL-5 and IL-13; Locksley, 2010; Scanlon and McKenzie, 2012; Bando et al., 2013; Barlow et al., 2013; Nussbaum et al., 2013). Environmental stimuli also activate afferent nerves in the airway epithelium that can themselves release biologically active peptide mediators and also trigger reflex release of acetylcholine from efferent fibers in the vagus nerve. This initial response is amplified by the recruitment and differentiation of subsets of T cells that sustain secretion of these cytokines and in some cases secrete another cytokine, IL-17, at specific strategic sites in the airway wall. The released cytokines act on epithelial cells and smooth muscle cells and drive the pathological responses of these cells that contribute to symptomatic disease. The cell biology underlying the responses of the relevant hematopoietic lineages is not specific to asthma and has been discussed elsewhere (Locksley, 2010; Scanlon and McKenzie, 2012). We focus our discussion on the contributions of epithelial cells and airway smooth muscle cells.
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Figure 1.

Cell–cell communication in the airway wall in asthma. Environmental triggers concurrently act on airway afferent nerves (which both release their own peptide mediators and stimulate reflex release of the bronchoconstrictor acetylcholine) and airway epithelial cells to initiate responses in multiple cell types that contribute to the mucous metaplasia and airway smooth muscle contraction that characterize asthma. Epithelial cells release TSLP and IL-33, which act on airway dendritic cells, and IL-25, which together with IL-33 acts on mast cells, basophils, and innate type 2 lymphocytes (iLC2). These secreted products stimulate dendritic cell maturation that facilitates the generation of effector T cells and triggers the release of both direct bronchoconstrictors and Th2 cytokines from innate immune cells, which feed back on both the epithelium and airway smooth muscle and further facilitate amplification of airway inflammation through subsequent adaptive T cell responses.

Cell biology of airway epithelium

The airway is covered with a continuous sheet of epithelial cells (Crystal et al., 2008; Ganesan et al., 2013). Two major airway cell types, ciliated and secretory cells, establish and maintain the mucociliary apparatus, which is critical for preserving airway patency and defending against inhaled pathogens and allergens. The apparatus consists of a mucus gel layer and an underlying periciliary layer. Ciliated cells each project ?300 motile cilia into the periciliary layer that are critical for propelling the mucus layer up the airway. In addition, cilia are coated with membrane-spanning mucins and tethered mucopolysaccharides that exclude mucus from the periciliary space and promote formation of a distinct mucus layer (Button et al., 2012). Secretory cells produce a different class of mucins, the polymeric gel-forming mucins. The two major airway gel-forming mucins are MUC5AC and MUC5B. Some secretory cells, known as mucous or goblet cells, produce mucins and store them within easily visualized collections of mucin granules, whereas other cells produce and secrete mucins (especially MUC5B) but lack prominent granules. Gel-forming mucins are secreted into the airway lumen and are responsible for the characteristic viscoelastic properties of the mucus gel layer.
Airway epithelial injury and remodeling in asthma

A variety of structural changes in the epithelium and other portions of the airway, termed “airway remodeling,” is frequently seen in individuals with asthma (Elias et al., 1999). These changes include airway wall thickening, epithelial hypertrophy and mucous metaplasia, subepithelial fibrosis, myofibroblast hyperplasia, and smooth muscle cell hyperplasia and hypertrophy. Airway remodeling is thought to represent a response to ongoing tissue injury caused by infectious agents, allergens, or inhaled particulates and by the host responses to these stimuli. Signs of frank epithelial injury, including loss of epithelial integrity, disruption of tight junctions, impairment of barrier function, and cell death, have been identified in some studies and may correlate with asthma severity (Laitinen et al., 1985; Jeffery et al., 1989; Barbato et al., 2006; Holgate, 2007). However, in many individuals asthma symptoms and features of airway remodeling, including mucous metaplasia and subepithelial fibrosis, are seen in the absence of signs of active airway infection or overt tissue injury (Ordoñez et al., 2000), suggesting that other processes account for the persistence of asthma in these individuals. Substantial evidence suggests that the persistence of asthma is driven by ongoing host immune responses that generate mediators driving airway remodeling and airway dysfunction. The epithelium is both a site of production of these mediators and a source of cells that respond to mediators produced by immune cells and other cells within the airway. How airway epithelial cells recognize and respond to viruses, allergens, and other stimuli has been comprehensively reviewed elsewhere (Lambrecht and Hammad, 2012). Here we will focus on the contribution of the epithelium to production of and responses to Th2 cytokines.
Airway epithelial contributions to Th2 responses.

Th2 cytokines, especially IL-13, play critical roles in asthma. Multiple cytokines, including TSLP, GM-CSF, IL-1, IL-25, and IL-33, are produced by the epithelium and promote production of Th2 cytokines by immune cells (Cates et al., 2004; Hammad et al., 2009; Locksley, 2010; Nagarkar et al., 2012). Genome-wide association studies implicate multiple Th2-related genes, including IL13, IL33, and TSLP, in asthma (Moffatt et al., 2010; Torgerson et al., 2011). IL-13 is produced by innate lymphoid cells (Neill et al., 2010; Price et al., 2010; Saenz et al., 2010; Hasnain et al., 2011) and Th2 cells (Grünig et al., 1998; Wills-Karp et al., 1998) during allergic inflammation and by macrophages in a mouse model of virus-induced airway disease (Kim et al., 2008). IL-13 induces characteristic changes in airway epithelial mRNA (Kuperman et al., 2005b; Woodruff et al., 2007; Zhen et al., 2007) and miRNA (Solberg et al., 2012) expression patterns in airway epithelial cells. The IL-13 transcriptional “signature” can be used to identify individuals with “Th2 high” and “Th2 low” asthma (Woodruff et al., 2009). The IL-13–induced protein periostin is secreted basally from airway epithelial cells and can be used as a biomarker for Th2 high asthma (Jia et al., 2012; Parulekar et al., 2014). Roughly half of individuals with asthma are Th2 high, and these individuals have better responses to treatment with inhaled corticosteroids (Woodruff et al., 2009) or anti–IL-13 antibody (Corren et al., 2011). The key drivers of Th2 low asthma remain poorly understood, although Th17 family cytokines may be important (Newcomb and Peebles, 2013).

Mucous metaplasia.

Although mucus is critical for host defense, pathological mucus production is an important contributor to asthma morbidity and mortality. In fatal asthma, airways are often plugged with tenacious mucus plugs that obstruct movement of gas (Kuyper et al., 2003). This catastrophic phenomenon likely reflects increased mucin production and secretion as well as changes in mucin cross-linking, mucus gel hydration, and mucus clearance. Abnormalities in mucus are not limited to severe asthma exacerbations because an increase in intracellular mucin stores (mucous metaplasia) is seen even in individuals with stable, mild to moderate asthma (Ordoñez et al., 2001). In mouse allergic airway disease models of asthma, mucous metaplasia results from increased production and storage of mucins (especially MUC5AC) in preexisting secretory cells, including club cells (Evans et al., 2004), rather than transdifferentiation of ciliated cells (Pardo-Saganta et al., 2013). However, in virus-driven models of asthma mucous cells might arise from transdifferentiation of ciliated cells (Tyner et al., 2006). A variety of stimuli and signaling pathways have been shown to regulate mucin production and secretion in airway epithelial cells.
IL-13 stimulates mucin production in Th2 high asthma.

Direct effects of IL-13 on airway epithelial cells induce mucous metaplasia in human airway epithelial cells in culture (Laoukili et al., 2001; Zhen et al., 2007) and in mouse airway epithelial cells in vivo (Kuperman et al., 2002). IL-13 is necessary for mucous metaplasia in many mouse asthma models (Grünig et al., 1998; Wills-Karp et al., 1998; Tyner et al., 2006). Individuals with Th2 high asthma have elevated levels of bronchial epithelial cell MUC5AC mRNA compared with healthy controls or individuals with Th2 low asthma (Woodruff et al., 2009). Recent transgenic mouse studies demonstrate roles for MUC5AC in clearance of enteric nematode infections (Hasnain et al., 2011) and protection against influenza infection (Ehre et al., 2012). Increased MUC5AC expression is therefore part of an integrated immune response that contributes to host defense against pathogens or inhaled particulates. A less well-recognized feature of Th2-high asthma is the substantial decrease in expression of MUC5B (Woodruff et al., 2009). The recent discovery that MUC5B is required for normal mucociliary clearance and defense against airway infection (Roy et al., 2014) suggests further attention should be directed to the possibility that a reduction in MUC5B may be an important contributor to airway dysfunction in asthma.

IL-13 is recognized by cell surface receptors expressed on almost all cell types, including airway epithelial cells (Fig. 2). The airway epithelial cell IL-13 receptor that is critical for mucous metaplasia is a heterodimer composed of IL-13R?1 and IL-4R?. Removal of this receptor in airway epithelial secretory cells (driven by the CCSP promoter) prevented mucous metaplasia in an allergic asthma model (Kuperman et al., 2005a). IL-13 binding leads to activation of Jak kinases associated with the receptor cytoplasmic domain and subsequent phosphorylation of signal transducer and activator of transcription 6 (STAT6). STAT6 activation is required for IL-13–induced mucous metaplasia (Kuperman et al., 2002).
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Figure 2.

Mechanisms of IL-13–induced mucous metaplasia. IL-13 binds to its receptor on the surface of mucous cell progenitors (e.g., club cells) leading to phosphorylation of STAT6 and translocation of STAT6 heterodimers to the nucleus, where they bind to promoters of STAT6-responsive genes. STAT6-dependent processes that contribute to mucous metaplasia include a CLCA1-dependent pathway, a Serpin-dependent pathway, and a 15-lipoxygenase-1–dependent pathway. The transcription factor SPDEF is a master regulator of mucous cell differentiation. It inhibits FOXA2, which represses mucous cell differentiation, and activates transcription of other genes that are expressed in mucous cells.

The series of events that link STAT6 activation to mucous metaplasia are only partly understood. STAT6 does not appear to directly regulate MUC5AC transcription (Young et al., 2007) and the critical direct targets of STAT6 have not been determined. One pathway that depends upon STAT6 activation involves the protein calcium-activated chloride channel 1 (CLCA1). CLCA1 is among the most highly induced genes in airway epithelial cells from individuals with asthma (Hoshino et al., 2002; Toda et al., 2002). Despite its name, CLCA1 does not appear to function as an ion channel but instead undergoes extracellular secretion and cleavage. Extracellular CLCA1 can induce MUC5AC expression via activation of the MAP kinase MAPK13 (p38?-MAPK; Alevy et al., 2012), although the presumed CLCA1 receptor and the relevant MAPK13 targets have not yet been identified. A second pathway involves the protease inhibitor Serpin3a, the mouse orthologue of human SERPINB3 and SERPINB4. These serpins are induced by IL-13 in a STAT6-dependent fashion (Ray et al., 2005). After allergen challenge, Serpin3a?/? mice had less mucous metaplasia than wild-type mice (Sivaprasad et al., 2011), despite an intact inflammatory response. These results suggest that serpins inhibit proteases that normally degrade one or more proteins required for mucous metaplasia, although the relevant proteases and their protein substrates are not yet known. Another IL-13–induced pathway involves the enzyme 15-lipoxygenase-1 (15-LO-1; Zhao et al., 2009). 15-LO-1 converts arachidonic acid to 15-hydroxyeicosatetraenoic acid, which was shown to enhance MUC5AC expression in human airway epithelial cells.

IL-13– and STAT6-mediated mucous metaplasia depends upon changes in the activity of a network of transcription factors. Allergen-induced IL-13–mediated STAT6 activation leads to increased expression of the SAM-pointed domain–containing Ets-like factor (SPDEF; Park et al., 2007; Chen et al., 2009). The induction of SPDEF depends at least in part on FOXM1, a member of the Forkhead box (FOX) family of transcription factors (Ren et al., 2013). The SPDEF program is also important for mucous metaplasia triggered by other stimuli, including rhinoviruses (Korfhagen et al., 2012). Although SPDEF does not appear to directly regulate mucin gene transcription, SPDEF initiates a transcriptional program that is necessary and sufficient to induce mucous metaplasia. One of the effects of SPDEF is inhibition of the expression of another FOX family gene, FOXA2. In mice, deletion of Foxa2 in mucous cell precursors is sufficient to induce mucous metaplasia, and overexpression of FOXA2 inhibits allergen-induced mucous metaplasia (Zhen et al., 2007; G. Chen et al., 2010). The relationship between IL-13 and FOXA2 is complex. IL-13 inhibits expression of FOXA2, which contributes to mucous metaplasia. However, deletion of Foxa2 in airway epithelial cells during fetal development resulted in Th2 inflammation and production of IL-13 in the airway (G. Chen et al., 2010). The direct targets that are responsible for these effects of FOXA2 are not yet known.
The EGFR pathway induces mucin gene expression and mucous metaplasia.

Epidermal growth factor receptor (EGFR) binds multiple ligands including EGF, TGF-?, heparin-binding EGF, amphiregulin, ?-cellulin, and epiregulin. Ligand binding activates the EGFR kinase domain, initiating signaling cascades that are central to many fundamental biological processes, including cell proliferation, differentiation, survival, and migration. EGFR ligands induce expression of MUC5AC in human airway epithelial cell lines and a tyrosine kinase inhibitor that inhibits EGFR kinase prevents mucous metaplasia induced either by an EGFR ligand or by allergen challenge (Takeyama et al., 1999). Subsequent studies showed that bronchial epithelial EGFR levels are increased in asthma and correlate with disease severity (Takeyama et al., 2001a), and that epithelial EGFR signaling contributes to mucous metaplasia in a chronic asthma model (Le Cras et al., 2011).

Various stimuli, including bacterial products (Kohri et al., 2002; Lemjabbar and Basbaum, 2002;Koff et al., 2008), viruses (Tyner et al., 2006; Zhu et al., 2009; Barbier et al., 2012), cigarette smoke (Takeyama et al., 2001b; Basbaum et al., 2002), and inflammatory cell products (Burgel et al., 2001) can activate the EGFR pathway in airway epithelial cells. Some stimuli have been shown to initiate the EGFR signaling cascade by activating the PKC isoforms PKC ? and PKC ?, leading to recruitment of the NADPH oxidase subunits p47phox and p67phox to membrane-associated dual oxidase-1 and the generation of reactive oxygen species (ROS) at the cell surface (Shao and Nadel, 2005). ROS in turn activate latent TGF-?–converting enzyme resulting in cleavage of surface EGFR pro-ligands (Shao et al., 2003). EGFR ligand binding leads to activation of the Ras–Raf–MEK1/2–ERK1/2 pathway and MUC5AC transcriptional induction, which depends upon the Sp1 transcription factor and Sp1-binding sites within the MUC5AC promoter (Takeyama et al., 2000; Perrais et al., 2002). The IL-13 and EGFR pathways make critical but distinct contributions to gene regulation in airway epithelial cells (Zhen et al., 2007). Both pathways inhibit expression of FOXA2, suggesting that this transcription factor may represent a final common pathway for IL-13– and EGFR-induced mucous metaplasia.

Notch signaling regulates mucous cell differentiation.

Notch signaling is also important for mucous metaplasia (Tsao et al., 2011). Notch is a transmembrane receptor that binds to cell-surface ligands in the Delta-like and Jagged families. Ligand binding activates ?-secretase–mediated proteolytic cleavage and liberates the Notch intracellular domain, which enters the nucleus, associates with transcription factors, and drives expression of downstream Notch genes. Genetic manipulation of Notch signaling in mice has different effects depending on the developmental stage. In explanted embryonic lungs, addition of Notch ligand or expression of a constitutively active form of Notch increased MUC5AC-containing mucous cells, whereas a ?-secretase inhibitor reduced mucous cells (Guseh et al., 2009). Notch-induced mucous metaplasia did not require STAT6 activation, suggesting that the Notch and STAT6 pathways may operate in parallel. In contrast, in postnatal mouse lung, disruptions of Notch signaling induced mucous metaplasia (Tsao et al., 2011), a process that principally depends on the Notch ligand Jagged1 (Zhang et al., 2013). The Notch target Hes1 appears to be critical for inhibition of mucous metaplasia and MUC5AC transcription, although inactivation of Hes1 was not sufficient to induce mucous metaplasia (Ou-Yang et al., 2013). The observation that a ?-secretase inhibitor reduced IL-13–induced mucous metaplasia in cultured human airway epithelial cells (Guseh et al., 2009) suggests that further attention to the role of epithelial Notch signaling in asthma is warranted.

The secretory pathway in mucous cells

Mucin monomers are large (?5,000 amino acid residue) proteins that require extensive processing in the ER and Golgi. Each mucin monomer contains ?200 cysteine residues that can potentially participate in intra- and intermolecular disulfide bonds. The ER of mucous cells contains specialized molecules that are not widely expressed in other cell types and are required for efficient processing of mucins. One of these is anterior gradient 2 (AGR2) homologue, a member of the protein disulfide isomerase family. An active site cysteine residue in AGR2 forms mixed disulfide bonds with mucins in the ER and mice deficient in AGR2 have profound defects in intestinal mucin production (Park et al., 2009). In a mouse model of allergic asthma, AGR2-deficient mice had reduced mucus production compared with allergen-challenged wild-type mice (Schroeder et al., 2012). The reduction in mucus production was associated with activation of the unfolded protein response, a characteristic response to ER stress (Walter and Ron, 2011). AGR2 may therefore either have a direct role in mucin folding or another function necessary for maintaining normal function of the mucous cell ER. Another molecule found in the mucous cell ER is inositol-requiring enzyme 1? (IRE1?), a transmembrane ER stress sensor. IRE1? is found in mucus-producing cells in the intestine and the airways, but not in other cells. IRE1? regulates AGR2 transcription, and mice deficient in IRE1? had reduced AGR2 expression and impaired airway mucin production in an allergic asthma model (Martino et al., 2013). AGR2 and IRE1? have apparently evolved to meet the unusual demands posed by the need to produce large amounts of mucins.

ORMDL3, a member of the Orm family of transmembrane ER proteins, has also been implicated in asthma. Genetic polymorphisms at loci close to ORMDL3 were strongly associated with asthma in multiple genome-wide association studies (Moffatt et al., 2007; Galanter et al., 2008). Allergen challenge induced ORMDL3 expression in airway epithelial cells in a STAT6-dependent fashion, although ORMDL3 does not appear to be a direct target of STAT6 (Miller et al., 2012). Studies involving overexpression or knockdown of ORDML3 in HEK293 cells indicate that ORMDL3 is involved in regulating ER stress responses and ER-mediated calcium signaling (Cantero-Recasens et al., 2010). In addition, Orm proteins form complexes with serine palmitoyl-CoA transferase (SPT), the first and rate-limiting enzyme in sphingolipid production, and may thereby help coordinate lipid metabolism in the secretory pathway (Breslow et al., 2010). Genetic and pharmacologic reductions in SPT activity induced airway hyperresponsiveness in the absence of inflammation or mucous metaplasia (Worgall et al., 2013). Further studies are required to determine whether ORMDL3’s role in modulating sphingolipid production, ER stress, calcium signaling, or other ER functions in airway epithelial cells or other cells is important in asthma.

Mucins travel from the ER to the Golgi and then are packaged into large granules for secretion. In the Golgi, mucins are extensively O-glycosylated and undergo further multimerization before being released from the cell by regulated exocytosis. Throughout the airways of normal mice and in distal (smaller) airways of humans, basal secretion accounts for most mucin release, and mucin-producing cells retain too little mucin to detect using histological stains. However, mucous cells found in larger airways of humans and allergen-challenged mice contain readily detectable accumulations of mucin-containing granules that can be released by various stimuli, including the P2Y2 receptor ligands ATP and UTP and proteases that cleave protease-activated receptors. Mice lacking the exocytic priming protein Munc13-2 accumulate mucin in secretory cells that normally have minimal intracellular mucin (club cells) but can secrete mucin in response to stimulation (Zhu et al., 2008). In contrast, allergen-challenged mice lacking the low affinity calcium sensor synaptotagmin-2 have a severe defect in acute agonist-stimulated airway mucin secretion, but have preserved basal secretion and do not accumulate mucins in club cells (Tuvim et al., 2009). Agonist-stimulated secretion also depends upon the IL-13–inducible calcium-activated chloride channel TMEM16A, which is increased in mucous cells from individuals with asthma (Huang et al., 2012). Because increased production of MUC5AC via transgenic overexpression was not in itself sufficient to cause airway obstruction (Ehre et al., 2012), it seems likely that qualitative defects in mucin processing, secretion, or hydration that affect the physicochemical properties of mucus contribute to airway obstruction in asthma. Epithelial transport of water and ions, including H+ and bicarbonate, is important in maintaining the normal properties of mucus (E. Chen et al., 2010; Paisley et al., 2010; Garland et al., 2013). Rapid secretion of stored mucin, which is not fully hydrated, may result in the formation of concentrated, rubbery mucus that cannot be cleared normally by cilia or by coughing (Fahy and Dickey, 2010). Hence, IL-13 (Danahay et al., 2002; Nakagami et al., 2008) and other asthma mediators that affect airway epithelial cell water and ion transport could contribute to airway obstruction by altering the physicochemical properties of mucus.
Ciliated cell structure and function in asthma

In comparison with the extensive asthma literature regarding mucous cells, relatively few reports have focused on ciliated cells. One study of epithelial cell strips obtained by endobronchial brushing found decreased ciliary beat frequency and increases in abnormal ciliary beating patterns and ciliary ultrastructural defects in individuals with asthma compared with healthy controls (Thomas et al., 2010). These abnormalities were more pronounced in severe asthma. Ciliary abnormalities were accompanied by increases in the numbers of dead cells and evidence of loss of epithelial structural integrity, which suggests that ciliary dysfunction may be a consequence of a generalized epithelial injury. In any case, these results suggest that ciliary dysfunction might be an important contributor to impaired mucociliary clearance in asthma.
Cell biology of airway smooth muscle in asthma

The excessive airway narrowing that can lead to severe shortness of breath, respiratory failure, and death from asthma is largely due to contraction of the bands of smooth muscle present in the walls of large- and medium-sized conducting airways in the lung. In the large central airways of humans, these bands of muscle are present in the posterior portion of the airways and attach to the anterior airway cartilage rings, but in more peripheral airways smooth muscle is present circumferentially around the airways. In both locations, contraction of smooth muscle, which can be physiologically induced by release of acetylcholine from efferent parasympathetic nerves or by release of histamine and cysteinyl leukotrienes from mast cells and basophils, causes airway narrowing, with the most extensive narrowing in medium-sized airways. In healthy mammals, including humans, physiological responses to release of acetylcholine from efferent nerves or release of histamine and leukotrienes from mast cells and basophils causes only mild and generally asymptomatic airway narrowing. Normal mammals are also generally resistant to marked airway narrowing in response to pharmacologic administration of high concentrations of these contractile agonists directly into the airways. However, people with asthma have a marked increase in sensitivity to all of these agonists that can readily be demonstrated by dramatic increases in airway resistance and associated drops in maximal expiratory airflow rates during forced expiratory maneuvers (Boushey et al., 1980). Recent comparisons between responses to inhaled allergens in allergic asthmatic subjects and other subjects with similarly severe cutaneous immune responses to allergens makes it clear that all allergic humans release largely similar amounts of bronchoconstrictors into the airways (i.e., histamine and leukotrienes), but only asthmatics develop exaggerated airway narrowing in response to these mediators (Becky Kelly et al., 2003).
Mechanisms regulating generation of force by airway smooth muscle actin–myosin coupling

Force generation by airway smooth muscle is mediated by interactions between actin and myosin that depend on phosphorylation of the myosin light chain by the serine–threonine kinase, myosin light chain kinase (Fig. 3). This process is negatively regulated by myosin phosphatase. Increases in intracellular calcium concentration in smooth muscle cells induce contraction by two parallel pathways. When bound to calcium, the serine–threonine kinase calmodulin directly phosphorylates, and thereby activates, myosin light chain kinase. Increased calcium also increases GTP loading of the GTPase, RhoA, which increases the activity of its downstream effector kinases Rho-associated coiled-coil–containing protein kinases 1 and 2 (ROCK 1 and 2). ROCKs directly phosphorylate myosin light chain phosphatase, an effect that inactivates the phosphatase, further enhancing myosin phosphorylation. RhoA can also be activated independently of increases in intracellular calcium.

Core signaling pathways responsible for airway smooth muscle contraction. Airway smooth muscle contractile force is generated by cyclic cross-bridging of actin and smooth muscle myosin, which depends on myosin phosphorylation. Myosin phosphorylation is regulated by cyclic increases in cytosolic calcium (Ca2+) that activate calmodulin (CaM) to phosphorylate myosin light chain kinase (MLCK), which directly phosphorylates myosin. In parallel, the small GTPase, RhoA, is activated by both calcium-dependent and -independent pathways. Rho directly activates Rho-associated coiled-coil protein kinase (ROCK) which, in turn, phosphorylates and thereby inactivates myosin light chain phosphatase (MLCP), which normally dephosphorylates myosin. The most important physiological pathway for increasing cytosolic calcium in airway smooth muscle involves activation of G?q by G protein–coupled receptors that respond to extracellular contractile agonists, such as methacholine (Mch), serotonin (5-HT), and histamine. G?q activates phospholipase C ? (PLC?), which generates IP3 to bind to IP3 receptors on the sarcoplasmic reticulum and release sequestered Ca2+.

There are multiple upstream paths to increased i[Ca] in airway smooth muscle. Acetylcholine, released from post-ganglionic parasympathetic efferent nerves that innervate the muscle, activates G protein–coupled M2 muscarinic receptors, which are coupled to G?q. GTP-loaded G?q activates its downstream effector, PLC?, which phosphorylates PIP2 to generate IP3. IP3, in turn, binds to IP3 receptors on the sarcoplasmic reticulum to trigger translocation of calcium into the cytosol. Other contractile agonists, including histamine, bradykinin, and serotonin (5-HT; the specific agonists and receptors vary across mammalian species) bind to different G protein–coupled receptors to trigger the same pathway. Agonist-induced airway smooth muscle contraction is usually associated with cyclic oscillations in i[Ca], thought to be induced by local changes in cytosolic calcium triggering reuptake of calcium by the sarcoplasmic reticulum, and the magnitude of contractile force induced is most closely associated with the frequency of these calcium oscillations rather than their amplitude (Bergner and Sanderson, 2002).

Increases in cytosolic calcium concentration can also be induced by an influx of calcium from the extracellular space, generally due to the opening of voltage-gated calcium channels in the plasma membrane. These channels can be opened experimentally by increasing the extracellular concentration of potassium ions, which also induces airway smooth muscle contraction. Increased extracellular potassium concentrations also increase release of acetylcholine from post-ganglionic efferent nerves, so proper interpretation of the effects of KCl requires simultaneous addition of a muscarinic antagonist such as atropine.
Regulation of airway smooth muscle force generation by integrin-containing adhesion complexes

For smooth muscle cell contraction to be translated into the force required for airway narrowing, the contracting smooth muscle cell must be firmly tethered to the underlying ECM. Linkage to the ECM is accomplished through the organization of multi-protein complexes nucleated by integrins. The short cytoplasmic domains of integrins can organize surprisingly large multi-protein machines that modulate multiple signaling pathways and link integrins (and thus their ECM ligands) to the actin–myosin cytoskeleton (Yamada and Geiger, 1997; Zaidel-Bar et al., 2007). Many of the contractile agonists that stimulate myosin phosphorylation and actin–myosin interaction simultaneously enhance the formation of integrin signaling complexes, induce actin polymerization at sites of adhesion, and strengthen coupling between the actin–myosin cytoskeleton and the ECM (Mehta and Gunst, 1999; Tang et al., 1999, 2003; Gunst and Fredberg, 2003; Gunst et al., 2003; Opazo Saez et al., 2004). These events appear to also be quite important for generation of maximal contractile force because interventions that inhibit the formation or activity of adhesion complexes can inhibit the strength of contraction without affecting myosin phosphorylation (Mehta and Gunst, 1999; Tang et al., 2003; Opazo Saez et al., 2004).
Lessons from abnormal behavior of airway smooth muscle in animal models
Mice lacking ?9?1 integrin in airway smooth muscle.

Although there are large differences between the organization of airways in mice and humans, in vivo abnormalities in airway narrowing seen in mouse models do provide some insight into pathways that potentially contribute to abnormal airway smooth muscle contraction in asthma. For the purposes of this review, we will cite three illustrative examples. The integrin ?9?1 is highly expressed in airway smooth muscle (Palmer et al., 1993). Conditional knockout of the integrin ?9 subunit (uniquely found in the ?9?1 integrin) results in a spontaneous increase in in vivo airway responsiveness (as measured by increases in pulmonary resistance in response to intravenous acetylcholine), and to increased contractile responses to cholinergic agonists of both airways in lung slices and tracheal rings studied in an organ bath (Chen et al., 2012). Interestingly, although tracheal rings from these mice also have increased contractile responses to other G protein–coupled receptor agonists (e.g., serotonin), they have normal contractile responses to depolarization with KCl. These findings suggest that loss of ?9?1 increases airway responsiveness at some step upstream of calcium release from the sarcoplasmic reticulum (Fig. 4 A). In this case, increased airway responsiveness appears to be due to loss of co-localization of the polyamine-catabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT), which binds directly to the ?9 cytoplasmic domain (Chen et al., 2004), and the lipid kinase, PIP5K1?, which binds directly to talin, an integrin ?1 subunit binding partner. Spermine and spermidine are critical cofactors for PIP5K1?, so its juxtaposition with SSAT effectively reduces enzymatic activity. PIP5K1? converts PI4P to PIP2 and is responsible for most of the PIP2 produced in airway smooth muscle cells (Chen et al., 1998). PIP2 is the substrate for IP3 generation by PLC?, so when ?9?1 is present and ligated, contractile agonists that activate receptors coupled to G?q induce less IP3 generation (Chen et al., 2012) and thus less Ca2+ release through IP3 receptors in the sarcoplasmic reticulum. The importance of this pathway was confirmed by the observations that the frequency of Ca2+ oscillations induced by cholinergic agonists was reduced in lung slices from mice lacking ?9?1, and that all of the abnormalities in smooth muscle from these animals could be rescued by addition of a cell-permeable form of PIP2 (Chen et al., 2012).

Pathways that negatively regulate airway smooth muscle contraction. (A) The integrin ?9?1 negatively regulates airway smooth muscle contraction by colocalizing the polyamine-catabolizing enzyme, spermine spermidine acetyltransferase (SSAT), which directly binds to the ?9 subunit with the lipid kinase, PIP5K1?, the major source of PIP2 in airway smooth muscle, which binds to talin, a direct interactor with the ?1 subunit. PIP5K1? depends on spermine and spermidine for maximal activity, so the local breakdown of spermine and spermidine reduces PIP5K1? activity, thereby decreasing PIP2 concentrations and the amount of IP3 that is generated by activation of contractile G protein–coupled receptors (such as those activated by acetylcholine or serotonin [5-HT]). (B) The secreted scaffold protein, milk fat globule-EGF factor 8 (MFGE8), inhibits the smooth muscle hypercontractility induced by IL-13, IL-17, and tumor necrosis factor ? (TNF) by inhibiting the induction and activation of the small GTPase, RhoA. Active RhoA contributes to smooth muscle contraction by directly activating Rho-associated coiled-coil protein kinase (ROCK) which, in turn, phosphorylates and thereby inactivates myosin light chain phosphatase (MLCP), which normally dephosphorylates myosin.
Effects of T cell cytokines on airway smooth muscle contractility.

Several studies conducted over the past 15 years have suggested that cytokines released from T cells can contribute to airway hyperresponsiveness in allergic asthma (Locksley, 2010). The Th2 cytokine IL-13 has been most extensively studied, and can induce both mucous metaplasia and airway hyperresponsiveness when administered directly into the airways of mice (Grünig et al., 1998; Wills-Karp et al., 1998). In vitro, incubation of tracheal rings or lung slices increases narrowing of airways in lung slices and increases force generation by mouse tracheal rings, at least in part by inducing a dramatic increase in expression of the small GTPase, RhoA (Chiba et al., 2009), which is a critical effector of airway smooth muscle contraction (Fig. 4 B). Chronic allergen challenge or direct administration of IL-13 into the airways of mice also increased RhoA expression, in association with induction of airway hyperresponsiveness. A recent study suggested that IL-17 can also increase airway smooth muscle contractility and airway narrowing by induction of RhoA in airway smooth muscle cells (Kudo et al., 2012). In that study, mice lacking the ?v?8 integrin specifically on antigen-presenting dendritic cells were protected from allergen-induced airway hyperresponsiveness. These mice had the same degree of general airway inflammation and mucous metaplasia in response to allergen as wild-type control mice, but had a very specific defect in the generation of antigen-specific Th17 cells, an important source of IL-17 in lungs (Kudo et al., 2012). In vitro, IL-17 was shown to directly increase the contractility of mouse tracheal rings and to increase the levels of RhoA protein and its downstream effector, ROCK2, and to increase phosphorylation of the direct ROCK target, myosin phosphatase. Phosphorylation of myosin phosphatase inhibits its function, and IL-17 was also shown to consequently increase phosphorylation of myosin light chain kinase. Importantly, all of these biochemical effects were dramatically induced in vivo in airway smooth muscle of control mice in response to allergen sensitization and challenge, but all were markedly reduced in mice lacking ?v?8 on dendritic cells. Furthermore, tracheal rings removed from these knockout mice after allergen challenge had decreased in vitro contractility compared with rings from allergen challenged control mice, but this difference in contractility was eliminated by exogenous addition of IL-17. These findings strongly suggest that both IL-13 and IL-17 can contribute to airway hyperresponsiveness by directly inducing RhoA expression in airway smooth muscle (Fig. 4 B). Tumor necrosis factor ?, also implicated in asthma pathogenesis, has been shown to increase airway smooth muscle contractility by a similar mechanism (Goto et al., 2009).
Enhanced cytokine-mediated airway smooth muscle contraction in MFGE8-deficient mice.

Milk fat globule EGF factor 8 (MFGE8) is a secreted protein composed of two EGF repeats and two discoidin domains. MFGE8 was originally described to facilitate uptake of apoptotic cells by phagocytes (Hanayama et al., 2004). Mice lacking MFGE8 have normal baseline lung morphology and function, but have exaggerated airway responsiveness after allergen sensitization and challenge (Kudo et al., 2013). However, this abnormality did not appear to be related to any effects on reuptake of apoptotic cells. Immunostaining demonstrated that secreted MFGE8 was concentrated adjacent to airway smooth muscle. Tracheal rings removed from MFGE8 knockout mice had normal contractile responses at baseline, but had markedly enhanced contractile responses after overnight incubation with IL-13, and this increase in contractility could be rescued by addition of recombinant MFGE8 to the muscle bath. Importantly, rescue required the presence of at least one of the discoidin domains and of the integrin-binding RGD motif of the second EGF repeat. In mouse tracheal rings and cultured airway smooth muscle, loss of MFGE8 greatly enhanced the IL-13–induced increase in RhoA protein. These findings suggest that ligation of one or more RGD-binding integrins on airway smooth muscle by extracellular MFGE8 normally serves as a brake on cytokine-mediated RhoA induction and thereby limits maximal cytokine-induced airway hyperresponsiveness (Fig. 4 B). The specific integrin(s) involved in this response, the molecular mechanisms linking integrin ligation to inhibition of RhoA, and the role and binding partner(s) of the MFGE8 discoidin domains that are required for RhoA inhibition all remain to be determined.

Conclusions

Rapid progress has been made toward identifying epithelial and smooth muscle cell molecules and pathways that can produce many of the abnormalities found in individuals with asthma. Because these discoveries were made in diverse experimental systems, we still face major challenges in understanding how these molecules and pathways interact in vivo and in identifying the pathways that are most relevant in people with asthma. Asthma is a heterogeneous disease, and recent progress toward identifying subtypes with distinct pathophysiologic mechanisms promises to focus attention on certain pathways in epithelial and smooth muscle cells (Lötvall et al., 2011). It will be especially important to understand mechanisms underlying severe asthma. Approximately 5–10% of individuals with asthma have severe disease, with symptoms that persist despite standard therapy with bronchodilators and inhaled corticosteroids (Brightling et al., 2012). These individuals have high rates of asthma exacerbations leading to hospitalization and are at relatively high risk for fatal asthma attacks. Continued attention to the study of the cell biology of asthma will be crucial for generating new ideas for asthma prevention and treatment based on normalizing epithelial and smooth muscle function.

Aspirin Exacerbated Respiratory Disease

What is aspirin-exacerbated respiratory disease (AERD)

Aspirin-exacerbated respiratory disease (AERD) is a clinical tetrad of nasal polyps, chronic hypertrophic eosinophilic sinusitis, asthma and sensitivity to any medication that inhibits cyclooxygenase-1 (COX-1) enzymes, namely aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) Ingestion of aspirin, and most NSAIDs, results in a spectrum of upper and/or lower respiratory reactions, to include rhinitis, conjunctivitis, laryngospasm and bronchospasm.1,2 AERD affects 0.3-0.9% of the general population, but the prevalence rises to 10-20% of asthmatics and up to 30-40% in those asthmatics with nasal polyposis.3-7 The average age of onset is 34 years in a US study and is thought to be acquired between teenage to middle adulthood years with no ethnic predilection and rare familial associations.3-7 AERD is more commonly reported in females (57% vs. 43%).

Note from the WAF editorial board:  The WAF would like to acknowledge and thank  Rachel U. Lee1 and Donald D. Stevenson, Division of Allergy, Asthma & Immunology, Naval Medical Center Portsmouth, Portsmouth, VA, USA. and the Division of Allergy, Asthma & Immunology, Scripps Clinic, San Diego, CA, USA for their continued support to Asthma education,.

Genetic Basis of Asthma

Asthma is the most common chronic childhood disease in developed nations and its prevalence has increased in the world over the last 25 years. It is a complex disease with both genetic and environmental risk factors. Asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment. This article reviews the current state of the genetics of asthma in six categories, viz. epidemiology, management, aetiology, family and twin studies, segregation and linkage studies, and candidate genes and single nucleotide polymorphisms (SNPs).

Asthma is one of the most serious allergic diseases and the most common chronic childhood disease in developed nations1. It has been characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli2–4, increased infiltration of various inflammatory cells especially eosinophils into the airway, epithelial damage, airway smooth-muscle hypertrophy5, constriction, variable airway obstruction usually associated with inflammation in the conducting airways of the lungs6 and mucous hypersecretion in the bronchiolar walls of the lung7. Asthma is critically dependent on a series of cell adhesion molecule-mediated interactions between vascular endothelium and leukocytes7, leading to symptoms8 and elevation in total serum IgE9. It is manifested physiologically by widespread narrowing of the air passages and clinically by paroxysms of dyspnoea, cough, wheezing and tightness, provoked by one or more triggers such as physical exertion and airway irritants (cold, dry air, smoke, etc.)4,10. It is an episodic disease, with acute exacerbations interspersed with symptom-free periods. Typically, most attacks are short-lived, lasting minutes to hours, and clinically the patient seems to recover completely after an attack. However, there can be a phase in which the patients experience some degree of airway obstruction daily. This phase can be mild, with or without superimposed severe episodes, or can be much more serious, with severe obstruction persisting for days or weeks; the latter condition is known as “acute severe asthma”. In unusual circumstances, acute episodes can cause death4. Asthma exacerbations are characteristically worse at night and can progress to severe airflow obstruction, shortness of breath, and respiratory distress and insufficiency. Rarely, severe sequel such as hypoxic seizures, respiratory failure, and death can occur.

Here we review the latest information on the genetic basis of asthma which is one of the most intriguing diseases affecting people of all ages, gender, race and ethnicities. Familial and segregation studies have an important role in asthma aetiology and several candidate genes on all the human chromosomes play their roles in initiation and/or inhibition of different pathways of asthma disease.

Note from the WAF editorial board: We wish to acknowledge and thank Mahdi Bijanzadeh, Padukudru A. Mahesh,* and Nallur B. Ramachandra
at the Indian Journal of Medical Research for their dedication to Asthma education and research.

Conclusion and future prospects

Asthma is one of the most serious and intriguing allergic diseases. Asthma aggregates within families and is a complex multifactorial disease with the involvement of environment and genetic components. Our preliminary pedigree analysis revealed that autosomal recessive pattern of inheritance was prominent in asthma; parental consanguinity100 and serum intracellular cell adhesion molecule-1 (ICAM-1)101 was significantly associated with asthma, whereas the ABO blood system102, IL-4 and ADAM33 specific gene variants81, and serum E-selectin101 were not associated with asthma. More than 100 loci have been reported to be associated with asthma and there are also indications that mutation in a major gene can cause asthma. Due to an increasing number of current studies being done in genetics of asthma, there is an increasing list of inducer and inhibitor candidate genes for asthma. There are more than 100 candidate genes in every chromosome which are identified to have an association with asthma and the strength of association of these SNPs with asthma varies in different parts of the world. More studies are needed to determine the exact function of these genes, gene-gene interactions and the gene-environment interactions which are undoubtedly complex and remain elusive for the time being even with whole genome-wide association studies.

Further studies on asthma with the genomics data and tools, to map, identify the specific gene/s, and phenotype specific SNPs will help to unravel the pathways involved in asthma aetiology and employ pharmacogenomics to design better drugs for an individualized treatment plan. Thus with a fruitful interaction among researchers involved in pathophysiology, epidemiology, clinical research and genetics of asthma, this century holds promise for a better understanding of the pathology, diagnosis, prevention, treatment and management of asthma.

Making a Lung Replacement

Making a Lung Replacement by the NIH

Hot on the heels of progress toward a liver transplant substitute, researchers have made transplantable lung grafts for rats. The accomplishment could pave the way for the development of an engineered human lung.

Blood vessels are preserved in the decellularized lung matrix. Image courtesy of Petersen et al., Science.

Lungs have a limited ability to regenerate. The primary therapy for severely damaged lungs is currently lung transplantation—surgery to remove the lung and replace it with a healthy lung from a deceased donor. However, lung transplants are limited by the small number of donor organs available—not much more than 1,000 per year.

To be successful, an artificial lung would need to retain the complex branching geometry of the lung’s airways. It would also require a large network of small blood vessels to transport oxygen and nutrients throughout the structure. Decellularization—the process of removing cells from a structure but leaving a scaffold with the architecture of the original tissue—has shown some success in other organs, including heart and liver. A team of researchers led by Dr. Laura Niklason of Yale University set out to build on this recent progress and develop a similar approach for lungs. Their work was supported by NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS).

The researchers harvested lungs from adult rats. Treating the lungs with a mild detergent solution for 2 to 3 hours removed the cells but left the lung architecture intact, as reported in the early online edition of Science on June 24, 2010. A careful analysis showed that a matrix of proteins remained behind to hold the lung’s shape.

To see if they could repopulate the matrix with cells and engineer a functional lung, the researchers injected endothelial cells into the blood vessels and epithelial cells into airways. They kept the matrix for up to 8 days in a novel bioreactor that was designed to mimic the pressure changes and ventilation a lung would experience. The researchers found that the cells reseeded the surfaces of the matrix in their appropriate locations. This finding suggests that the decellularized matrix maintains cues for the cells to attach and thrive.

The researchers tested the engineered lungs in rats for short time intervals (45-120 min) and found that the lungs inflated with air, with only some modest bleeding into airways. Most importantly, the lungs successfully exchanged oxygen and carbon dioxide like natural lungs.

To see whether their method might apply to human tissues, the researchers got human lung segments from a tissue bank. They were able to decellularize the tissues while preserving their architecture. They then reseeded the matrices with epithelial and endothelial cells and found that they adhered at their appropriate locations. This result supports the idea that the approach holds promise for human lung tissue.

“We succeeded in engineering an implantable lung in our rat model that could efficiently exchange oxygen and carbon dioxide, and could oxygenate hemoglobin in the blood. This is an early step in the regeneration of entire lungs for larger animals and, eventually, for humans,” says Niklason. She notes that years of research with adult stem cells will likely be needed to develop ways to repopulate lung matrices and produce fully functional lungs for people.

—by Harrison Wein, Ph.D.
Related Links:

* Lung Transplant:
http://www.nhlbi.nih.gov/health/dci/Diseases/lungtxp/lungtxp_whatis.html