The research was done in mice, but it supports the “hygiene hypothesis”: the idea that bacteria are needed to shape a healthy immune system, and that our bacteria-fearing lifestyles are increasing levels of asthma, allergy and other autoimmune diseases.

In the study, which was published in the journal Science, the researchers compared normal mice with mice that were raised in special germ-free environments. They found high levels of special white blood cells called invariant natural killer T cells (iNKT) in the lungs and intestines of the germ-free mice.

These iNKT cells release proteins that cause inflammation and attract more inflammatory white blood cells. Inflammation plays an important role in many autoimmune diseases, and iNKT cells are known to be an active ingredient in asthma, which is in the lungs, and ulcerative colitis, an inflammatory disease of the bowel.

Even when exposed to normal bacteria later in life, the germ-free mice still had abnormally high levels of iNKT cells and diseased lungs and intestines. This indicated that an “immune priming event” happens very early in life and is essential for the proper formation of the immune system, the researchers said.

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Armed with the right information, physicians can play a stronger role in ensuring asthma patients don’t waver in taking drugs proven to prevent asthma attacks, according to researchers at Henry Ford Hospital in Detroit.

The study finds patients are more likely to routinely take inhaled corticosteroids (ICS) for asthma control when physicians kept close watch over their medication use and reviewed detailed electronic prescription information, including how often patients fill their prescriptions and the estimated number of days each prescription would last.

“Better inhaled corticosteroid adherence means better overall asthma control, and less hospitalization,” says lead study author L. Keoki Williams, M.D., MPH, Center for Health Services Research and Department of Internal Medicine at Henry Ford Hospital.

“Unfortunately, overall patient adherence to ICS medication is poor, accounting for an estimated 60 percent of asthma hospitalizations. So it’s important, as we move forward with health care reform, to look for more effective ways to make sure patients stay with their prescription regimens.”

The study – the first large-scale, controlled study to test the effectiveness of routinely providing patient medication adherence information to physicians – appears online in the Journal of Allergy and Clinical Immunology (www.jacionline.org).

ICS, taken using an inhaler, help prevent and reduce airway swelling, and are considered the cornerstone therapy for controlling persistent asthma in patients, says Dr. Williams.

The Henry Ford scientific team set out to design an intervention that would provide physicians information on the most recent national asthma guidelines and methods for discussing medication non-adherence with their patients.

The intervention also offered physicians electronic access to patients’ medication prescription fill/refill information via Henry Ford’s ePrescribing application, part of its electronic medical record system that allows physicians to prescribe and review patient medications electronically.

The study enrolled 193 Henry Ford primary care physicians (family medicine, internal medicine, pediatrics). Eighty-eight were randomly assigned to the intervention group, while 105 were assigned to the control group (no intervention).

Physicians in the intervention group used ePrescribing to track medication fills and refills. The application also offered physicians the option to take it one step further: To review detailed adherence data, including estimates of the proportion of time that the patients took their medication.

Medication adherence for both groups was measured by using both electronic prescriptions and pharmacy claims for medication fills and refills.

Researchers found ICS adherence to be very similar among patients in the intervention group and those in the control group (21.3 percent vs. 23.3 percent).

But adherence was significantly higher in the intervention group (35 percent) when the patient’s physician elected to view detailed adherence information via the ePrescribing application.

Few physicians, however, in the intervention group accessed the detailed adherence information. “Going forward, one of the obstacles will be finding time for physicians to review and discuss this information with patients in their typically busy practices,” says Dr. Williams.

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Could some cases of asthma actually be caused by an allergic reaction to a common environmental bacteria? New research findings published in the Journal of Leukocyte Biology suggests that this is a possibility. In a research report appearing in the February 2012 print issue, researchers show a link between common environmental bacteria and airway inflammation. Specifically, their research suggests that some strains of Pseudomonas aeruginosa cause white blood cells to produce very high levels of histamine, which in turn leads to inflammation, a hallmark symptom of asthma.

In this five minute interview with Dr. George Caughey, M.D. Chief, Pulmonary/Critical Care/Sleep Medicine Section San Francisco VA Medical Center and Professor of Medicine at University of California, San Francisco (UCSF) School of Medicine we discuss the key studies findings, potential treatment options and laboratory test for Pseudomonas Bacteria.

“We hope that these findings in mice will encourage human-focused research regarding bacterial stimulation of histamine production by white blood cells, like neutrophils, that are not traditionally associated with allergic inflammation,” said Dr. George Caughey, M.D., a researcher involved in the work. “Such research could improve our understanding of inflammation in bacterial infections, and help us to craft therapies for relief of inflammation and its consequences for short and long-term health,” he noted. To make this discovery, scientists studied the effect of two strains of pseudomonas bacteria on isolated mouse white blood cells tasked with killing bacteria, called neutrophils.

To make this discovery, scientists studied the effect of two strains of pseudomonas bacteria on isolated mouse white blood cells tasked with killing bacteria, called neutrophils. Results showed that one strain killed the neutrophils, but the second strain produced substances that caused the neutrophils to increase their production of histamine significantly. To see if their discovery was applicable outside of the test tube, the histamine-stimulating strain was then used to infect mice to produce bronchitis and pneumonia. These mice experienced a significant increase of histamine in their airways and lungs. Additional work showed that the bacteria persuade neutrophils to produce histamine by causing them to make much more of the key enzyme in histamine synthesis (histidine decarboxylase) than neutrophils would otherwise do in the unstimulated state.

“Despite advances in diagnosing and treating the symptoms of asthma and allergy, our understanding of the underlying initiating events remains elusive,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “This report helps shed light on how an ‘everyday organism’ might trigger asthma and allergy from an immune cell type not normally thought to be involved in allergic disease.”

About the Journal of Leukocyte Biology

The Journal of Leukocyte Biology (http://www.jleukbio.org) publishes peer-reviewed manuscripts on original investigations focusing on the cellular and molecular biology of leukocytes and on the origins, the developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes and other cells involved in host defense and inflammation. The Journal of Leukocyte Biology is published by the Society for Leukocyte Biology.

About George Caughey, M.D.

Dr. Caughey received an M.D. from Stanford. After Medicine and Pulmonary subspecialty training at Pennsylvania Hospital and UCSF, he trained in lung research at UCSF’s Cardiovascular Research Institute and at Genentech, joining UCSF’s pulmonary faculty in 1986. He occupies the Julius and Lillian Nadel Endowed Chair and is Chief of the Pulmonary and Critical Care Medicine Section at the San Francisco VA Medical Center. Major activities include laboratory-based research, teaching, inpatient and outpatient clinical consulting, and serving on editorial, administrative, and advisory committees.

Research Interests
Extracellular proteases influence the pathology of lung diseases. The lab is interested in the roles of known and novel proteases in normal and diseased lung, emphasizing roles in scarring, ion transport, and anti-bacterial defense. The lab’s traditional focus is on peptidases secreted by mast cells, which are resident inflammatory cells especially abundant in human lung. The lab characterized several of the major secreted mast cell serine proteases. Achievements include the first cloning of a tryptase and discovery of new functions of these enzymes as peptidases, secretagogues and modulators of muscle tone. These investigations encouraged pharmaceutical development of tryptase inhibitors. The lab characterized the multi-gene human tryptase locus, discovering novel genes encoding membrane-anchored (gamma) and truncated (delta) tryptases, as well as major polymorphisms and population-skewed inheritance of deficiency alleles like alpha and frame-shifted beta. A current thrust of research concerns clinical consequences of human variations in inheritance of mast cell tryptase genes.

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According to the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine, accelerated growth in the first three months of life, but not fetal growth, is associated with an increased risk of asthma symptoms in young children. a

“We know that low birth weight is associated with an increased risk of asthma symptoms in children, but the effects of specific fetal and infant growth patterns on this risk had not been examined yet,” said researcher Liesbeth Duijts, MD, PhD. “In our study, weight gain acceleration in early infancy was associated with an increased risk of asthma symptoms in children of preschool age, independent of fetal growth patterns, suggesting that early infancy might be a critical period for the development of asthma.”

This study was embedded in the Generation R Study, a population-based prospective cohort study, and included 5,125 children who were followed from fetal life through the age of four. Information on asthma symptoms was obtained by questionnaires at the ages of 1, 2, 3, and 4.

No consistent relationships between fetal length and weight growth during different trimesters and the development of asthma symptoms were observed. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms, including wheezing (overall odds ratio (OR) 1.44 (95% confidence interval (CI): 1.22, 1.70), shortness of breath: 1.32 (1.12, 1.56), dry cough: 1.16 (1.01, 1.34), and persistent phlegm: 1.30 (1.07, 1.58)). The associations between accelerated infant growth and risk of developing asthma symptoms were independent of other fetal growth patterns and tended to be stronger among children of atopic mothers.

“Our results suggest that the relationship between infant weight gain and asthma symptoms is not due to the accelerated growth of fetal growth-restricted infants only,” said Dr. Duijts. “While the mechanisms underlying this relationship are unclear, accelerated weight growth in early life might adversely affect lung growth and might be associated with adverse changes in the immune system.”

The study had a few limitations, including the possibility of measurement error in the estimation of fetal weight and the use of self-report for asthma symptoms.

“Further research is needed to replicate our findings and explore the mechanisms that contribute to the effects of growth acceleration in infancy on respiratory health,” concluded Dr. Duijts. “The effects of infant growth patterns on asthma phenotypes in later life should also be examined.”

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According to press reports, researchers analyzed data from more than 37,000 participants in the Norwegian Mother and Child Cohort Study in order to compare the health of children who were delivered by planned or emergency C-section with those who were born vaginally.

The results showed that children delivered by C-section had a slightly increased risk for asthma at age 3, but no increased risk for wheezing or frequent lower respiratory tract infections. The risk of asthma was highest among those whose mothers did not have allergies.

According to the Norwegian Institute of Public Health, “It is unlikely that a Cesarean delivery itself would cause an increased risk of asthma, rather that children delivered this way may have an underlying vulnerability,” study primary author Maria Magnus, a researcher at the department of chronic diseases.

Possible reasons for the increased risk of asthma among children delivered by C-section include an altered bacterial flora in their intestine that affects their immune system development, or the fact that these children are more likely to

While the study found an association between C-section birth and asthma, it did not demonstrate a cause and effect.

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A large subgroup of mild-to-moderate asthma is persistently non-eosinophilic

A large percentage of patients with mild-to-moderate asthma have persistently non-eosinophilic disease which may not respond to currently available anti-inflammatory treatments, according to a new study.

In a cross-sectional study of 995 asthmatic subjects enrolled in nine clinical trials conducted by the NHLBI’s Asthma Clinical Research Network, sputum eosinophilia (?2% eosinophils) was found in only 36% of asthmatics not using an inhaled corticosteroid (ICS) and 17% of those using an ICS. Among patients who achieved good asthma control, 26% had sputum eosinophilia, compared with 15% among patients who had not achieved good control.

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

Among asthmatic subjects not taking an ICS who had repeated induced sputum samples, 22% had sputum eosinophilia on every occasion (persistent eosinophilia), 31% had eosinophilia on at least one occasion (intermittent eosinophilia), and 47% had no eosinophilia on every occasion (persistently non-eosinophilic). Two weeks of treatment with a combination of anti-inflammatory drugs resulted in significant improvements in airflow obstruction in subjects with eosinophilic asthma, but not in those with persistently non- eosinophilic asthma. Bronchodilator responses to albuterol, however, were similar in eosinophilic and non-eosinophilic asthma.

“Prevalence estimates for non-eosinophilic asthma in earlier studies were based on single sputum samples,” said John Fahy, MD, MSc, professor of medicine and director of the Cardiovascular Research Institute/University of California San Francisco Airway Clinical Research Center. “Here we show for the first time that sputum eosinophilia is persistently absent in a large percentage of patients with mild/moderate asthma when sputum is analyzed repeatedly over time.”

The poor response to intense combined treatment seen in patients with persistently non-eosinophilic asthma suggests that these patients have a unique disease phenotype for which new treatments need to be developed. Treatment responses in patients with intermittent eosinophilia were similar to those of patients with persistent eosinophilia.

“A large subgroup of patients with mild-to-moderate asthma do not have the usual eosinophilic subtype that is responsive to steroid treatment,” concluded Dr. Fahy. “In addition to the implications for the care of these patients, our results have important implications for future asthma research. In clinical studies, the eosinophil phenotype of patients should be characterized to better understand treatment responses and disease mechanisms. In addition, appropriate in vitro and animal models for the study of the mechanisms of non-eosinophilic airway disease need to be developed.”

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Researchers at the University of Pittsburgh School of Medicine have identified a molecular pathway that helps explain how an enzyme elevated in asthma patients can lead to increased mucus production and inflammation that is characteristic of the lung condition. Their findings, reported online in this week’s Proceedings of the National Academy of Sciences, reveal unique interactions between biological molecules that could be targeted to develop new asthma treatments.

An enzyme called epithelial 15-lipoxygenase 1 (15LO1) metabolizes fatty acids to produce an eicosanoid known as 15 hydroxyeicosaetetranoic acid (15 HETE) and is elevated in the cells that line the lungs of asthma patients, explained Sally E. Wenzel, M.D., professor of medicine, Pitt School of Medicine, and director of the Asthma Institute at UPMC and Pitt School of Medicine. Her team showed in 2009 that the enzyme plays a role in mucus production.

“In this project, we found out 15 HETE is conjugated to a common phospholipid,” she said. “That complex, called 15HETE-PE, and 15LO1 behave as signaling molecules that appear to have a powerful influence on airway inflammation.”

By examining lung cells obtained by bronchoscopy from 65 people with asthma, the researchers found that both 15LO1 and 15HETE-PE displace an inhibitory protein called PEBP1 from its bond with another protein called Raf-1, which when freed can lead to activation of extracellular signal-regulated kinase(ERK). Activated ERK is commonly observed in the epithelial, or lung lining, cells in asthma, but until now the reason for that was not understood.

“This is an important study as it directly explores the important role of 15-lipoxygenase 1 in the airway epithelial cells of patients with asthma, which immediately establishes the relevance to human disease,” said Mark T. Gladwin, M.D., chief, Division of Pulmonary, Allergy and Critical Care Medicine, UPSOM.

Other experiments showed that knocking down 15LO1 decreased the dissociation of Raf-1 from PEBP1, which in turn reduced ERK activation. The pathway ultimately influences the production of factors involved in inflammation and mucus production.

“These results show us on both a molecular and mechanistic level and as mirrored by fresh cells from the patients themselves that the epithelial cells of people with asthma are very different from those that don’t have it,” Dr. Wenzel said. “It also gives us a potential treatment strategy: If we can prevent Raf-1 displacement, we might have a way of stopping the downstream consequences that lead to asthma.”

Co-authors include Jinming Zhao, Ph.D., Silvana Balzar, M.D., Claudette M. St. Croix, Ph.D., and John B. Trudeau, B.S., of UPSOM and the Asthma Institute; and Valerie B. O’Donnell Ph.D., of Cardiff University, United Kingdom. The study was funded by the National Institutes of Health and the American Heart Association.

Contact: Anita Srikameswaran
SrikamAV@upmc.edu
412-578-9193
University of Pittsburgh Schools of the Health Sciences
Pitt team finds molecular pathway that leads to inflammation in asthma
75.26.195.212

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When children with asthma get the flu, they often land in the hospital gasping for air. Researchers at Children’s Hospital Boston have found a previously unknown biological pathway explaining why influenza induces asthma attacks. Studies in a mouse model, published online May 29 by the journal Nature Immunology, reveal that influenza activates a newly recognized group of immune cells called natural helper cells – presenting a completely new set of drug targets for asthma.

If activation of these cells, or their asthma-inducing secretions, could be blocked, asthmatic children could be more effectively protected when they get the flu and possibly other viral infections, says senior investigator Dale Umetsu, M.D., Ph.D., of Children’s Division of Immunology.

Although most asthma is allergic in nature, attacks triggered by viral infection tend to be what put children in the hospital, reflecting the fact that this type of asthma isn’t well controlled by existing drugs.

“Virtually 100 percent of asthmatics get worse with a viral infection,” says Umetsu. “We really didn’t know how that happened, but now we have an explanation, at least for influenza.”

Natural helper cells were first, very recently, discovered in the intestines and are recognized to play a role in fighting parasitic worm infections as part of the innate immune system (our first line of immune defense).

“Since the lung is related to the gut – both are exposed to the environment – we asked if natural helper cells might also be in the lung and be important in asthma,” Umetsu says.

Subsequent experiments, led by first authors Ya-Jen Chang, Ph.D., and Hye Young Kim, Ph.D., in Umetsu’s lab, showed that the cells are indeed in the lung in a mouse model of influenza-induced asthma, but not in allergic asthma. The model showed that influenza A infection stimulates production of a compound called IL-33 that activates natural helper cells, which then secrete asthma-inducing compounds.

“Without these cells being activated, infection did not cause airway hyperreactivity, the cardinal feature of asthma,” Umetsu says. “Now we can start to think of this pathway as a target – IL-33, the natural helper cell itself or the factors it produces.”

Personalized medicine in asthma?

The study adds to a growing understanding of asthma as a collection of different processes, all causing airways to become twitchy and constricted. “In mouse models we’re finding very distinct pathways,” Umetsu says.

Most asthma-control drugs, such as inhaled corticosteroids, act on the best-known pathway, which involves immune cells known as TH2 cells, and which is important in allergic asthma. However, Umetsu’s team showed in 2006 that a second group of cells, known as natural killer T-cells (NKT cells), are also important in asthma, and demonstrated their presence in the lungs of asthma patients. NKT cells, they showed, can function independently of TH2 cells, for example, when asthma is induced with ozone, a major component of air pollution. Compounds targeting NKT cells are now in preclinical development.

The recognition now of a third pathway for asthma, involving natural helper cells, may reflect the diversity of triggers for asthma seen in patients.

“Clinically, we knew there were different asthma triggers, but we thought there was only one pathway for asthma,” Umetsu says, adding that all of the identified pathways can coexist in one person. “We need to understand the specific asthma pathways present in each individual with asthma and when they are triggered, so we can give the right treatment at the right time.”

The study was funded by the National Institutes of Health.

Children’s Hospital Boston is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children’s research community. Founded as a 20-bed hospital for children, Children’s Hospital Boston today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children’s also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Children’s, visit: http://vectorblog.org.

CONTACT:
Erin McColgan
Children’s Hospital Boston
617-919-3110
erin.mccolgan@childrens.harvard.edu

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Research into varying causes of asthma may eventually lead to new ideas on how to manage the condition.

According to an article published in the Scientific American, Asthma rates have been surging around the globe over the past three decades, and for a long time researchers thought they had a good idea of what might be fueling the increase: the world we live in is just a little too clean. According to this notion—known as the hygiene hypothesis—exposure in early childhood to infectious agents programs the immune system to mount differing highly effective defenses against disease-causing viruses, bacteria and parasites. Better sanitary conditions deprive the immune system of this training, so that for reasons that are still unclear, the body pounces on harmless particles—such as dust and ragweed—as if they were deadly threats. The resulting allergic reaction leads to the classic signs of asthma: chronic inflammation or swelling of the airways and acute spasms of those passageways.

Or so the thinking went. Although a lot of data support the hygiene hypothesis for allergies, the same cannot be said for asthma. Contrary to expectations, asthma rates have skyrocketed in urban areas in the U.S. that are not particularly clean. Moreover, the big increase in asthma rates in developed countries did not kick off until the 1980s—well after general sanitary conditions in the richer parts of the world had improved. And some studies are beginning to show that far from protecting children from asthma, respiratory infections in early childhood may actually be a risk factor for it.

The collapse of the hygiene hypothesis as a general explanation for the startling jump in asthma rates has led physicians and scientists to a new realization: asthma is a much more complex condition than anyone had truly appreciated. Indeed, it may not be even be a single disease. Studies now suggest that only half of asthma cases have an allergic component.

The prevention and treatment implications are significant. If, for instance, it is true that allergy is not a fundamental cause of asthma in many people, then an alternative mix of treatments may be more effective for those individuals. To root out asthma’s cause (or causes) and properly treat the burgeoning number of people who are affected—300 million globally at last count—scientists will have to come to grips with the biology of its various forms.

Balancing Act
The hygiene hypothesis was first described in 1989 by David P. Strachan, a British epidemiologist who was studying hay fever. The more children in a family, he noticed, the lower the rates of hay fever and eczema, an allergic skin condition. Children in large families tend to swap colds and other infections more often than children with fewer siblings. Could it be that increased exposure to pathogens from their many siblings was protecting children from large families against allergies?

That same year Erika von Mutius, an epidemiologist at Munich University, was looking into the effect of air pollution on asthma in what was then East and West Germany. Children from dirtier East Germany, she was shocked to find, had dramatically less asthma than their West German counterparts living in cleaner, more modern circumstances. The East German children, unlike their Western counterparts, had spent more time in day care and thus had likely been exposed to many more viruses and bacteria. “That was astonishing,” she recalls, and led to “a major shift” in thinking.

These findings sparked intense debate among scientists. What is it about unhygienic living that might protect against asthma? One of the more popular explanations in the following decades entailed a balance between the immune cells that are involved in the body’s reaction to most viruses and bacteria and those that are involved in the reaction to most parasites and allergens. These two groups of cells produce chemicals that inhibit each other. Early-childhood exposure to bacteria and viruses would cause the infection-related cells to become active, keeping the allergy- and parasite-related cells in check. Without that interplay, the allergy-related cells would later become over­reactive, starting an allergic chain reaction that became chronic and ended in constricted airways, asthmatic spasms and labored breathing.

Inconvenient Facts
There was only one problem. As more data came in, they failed to tell the same story as the hygiene hypothesis. Children in Latin America with high rates of supposedly protective infection have even higher rates of asthma than children in western Europe. Inner-city children in Chicago and New York have quite high rates of asthma, despite unhygienic living. And the rates of asthma varied among countries with very similar histories of cleanliness—indicating that there was more to it than tidiness. For example, by 2004 Sweden’s asthma cases had increased to 10 percent, according to one international study, while the number of cases in the U.K. had soared to 20 percent.

In addition, research showed that the relation between asthma and allergy is not at all straightforward. Some cases of asthma are indeed triggered by allergies, although the consensus among researchers over the past decade is that the connection is probably not as clear-cut as the hygiene hypothesis would suggest. Still other layers of immune regulation must be involved. Maria Yazdanbakhsh, a parasitologist at Leiden University in the Netherlands, has shown that people infected with parasitic worms have very high levels of the allergy-related immune cells but very low rates of asthma, disproving a direct connection between allergy and asthma in these cases at least.

What is more, a landmark review of asthma studies in 1999 by Neil Pearce, now at the London School of Hygiene and Tropical Medicine, demonstrated that at least half of asthma cases in the general population have no connection to allergic reactions at all. These could never be explained by the hygiene hypothesis.

In fact, the same factors that the hygiene hypothesis suggests protect people from developing allergic asthma may cause them to develop nonallergic asthma. “We think that dirt protects against allergic asthma, as foretold by the hygiene hypothesis, but increases the risk of having a nonallergic form,” says Laura Rodrigues of the London School of Hygiene and Tropical Medicine, who studies asthma in Latin America. Pollutants in the air can irritate the airways and cause inflammation that leads to constricted breathing. Childhood colds, which the hygiene hypothesis suggested might help prevent development of asthma, can actually be a risk factor for asthma, especially if severe, says James E. Gern, a pediatrician who studies colds and asthma at the University of Wisconsin–Madison. “Early-life infections are an indicator of asthma risk rather than protective in any way,” he says.

Besides the hygiene hypothesis, what can explain the increase in asthma rates? Other suggested causes include a rise in sedentary lifestyle, which could affect lung strength, and the rise in obesity, which increases inflammation throughout the body. A reworking of the hygiene hypothesis that focuses on changes in the normal nondisease-causing bacteria that live inside and on the body (in the intestines or the airways or on the skin) has promise. Studies by von Mutius and others have shown that children who live on farms where cows or pigs are raised and where they drink raw milk almost never have asthma, allergic or otherwise. Presumably because the children drank unpasteurized milk and handled livestock, they have different strains of normal bacteria in their airways that are somehow more protective than those found in city kids.

But the short answer to the question of why asthma has increased, according to Pearce, von Mutius, Rodrigues and many others, is, “We don’t know.” Pearce, in particular, wonders whether modernization in general or westernization in particular may play a role. “There is something about westernization that means people’s immune systems function in a different way,” he says. “But we don’t know what the mechanism is.”

Getting at the true underlying cause of the climb will require better ways of distinguishing among various possible types of asthma. Major asthma research networks supported by the National Institutes of Health have begun recording the details of thousands of individuals’ symptoms and treatments. As the results are gathered and analyzed, researchers hope to identify clusters of asthma cases that have different causes and respond to different treatments. The hope is that “if you come in with these characteristics in asthma, we can anticipate what the prognosis is going to be and what the most effective treatment for you is going to be,” says William W. Busse of the University of Wisconsin School of Medicine and Public Health, who is part of one such network.
It will take years to understand fully whether microbial exposure, lifestyle changes or the obesity epidemic is more important in explaining the continuing increase in asthma rates. But one thing is clear: the hygiene hypothesis was just the beginning.

To subscribe to the Scientific American and for more information about the Asthma article visit http://www.scientificamerican.com/article.cfm?id=why-are-asthma-rates-soaring&page=3

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ANAHEIM, — In what they described as the opening of a new era in the development of potentially life-saving new drugs, scientists today reported discovery of a way to tone down an overactive gene involved in colon cancer and block a key protein involved in asthma attacks. Those targets long had ranked among hundreds of thousands that many scientists considered to be “undruggable,” meaning that efforts to reach them with conventional medicines were doomed to fail.

“These substances represent an entirely new class of potential drugs,” study leader Gregory Verdine, Ph.D., told the 241st National Meeting & Exposition of the American Chemical Society, being held here this week. “They herald a new era in the drug-discovery world.”

Verdine cited estimates that conventional medicines, most of which belong to a family termed “small molecules,” cannot have any effect on 80-90 percent of the proteins in the body known to be key players in disease. Throwing up their hands in frustration, scientists had even begun to term these prime targets for battling disease as “untouchables” and “undruggable.”

The new substances are not small molecules, but “stapled peptides,” named because they consist of protein fragments termed peptides outfitted with chemical braces or “staples.” The stapling gives peptides a stronger, more stable architecture and the ability to work in ways useful in fighting disease.

“Our new stapled peptides can overcome the shortcomings of drugs of the past and target proteins in the body that were once thought to be undruggable,” Verdine said. “They are a genuinely new frontier in medicine.”

In one advance, Verdine and colleagues at Harvard University described development of the first stapled peptides that target colon cancer and asthma attacks. The colon cancer stapled peptides inhibit activity of a protein called beta-catenin that, when present in a hyperactive form, causes cells to grow in an aggressive and uncontrolled way. That protein normally helps keep certain cells, including those lining the colon, in good health. But the abnormal protein has been directly linked with an increased risk of colon cancer and other types of cancer, including those of the skin, brain, and ovaries.

When added to human colon cancer cells growing in laboratory cultures, the stapled peptides reduced the activity of beta-catenin by 50 percent. In patients, that level of reduction could be sufficient to have a beneficial impact on the disease, Verdine suggested.

Verdine also reported development of the first stapled cytokines, which show promise for fighting asthma. Cytokines are hormone-like proteins secreted by cells of the immune system and other body systems that help orchestrate the exchange of signals between cells. The stapled cytokines moderate the activity of a cytokine called interleukin-13, which asthma patients produce in abnormally large amounts that contribute to asthma attacks.

Current asthma drugs, he noted, tend to treat the underlying symptoms of asthma, particularly inflammation. By contrast, stapled cytokines could treat the underlying causes of the disease. Verdine’s team is collaborating with a pharmaceutical firm on efforts to further develop the stapled peptides.

The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With more than 163,000 members, ACS is the world’s largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.M

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