Tag: regulation

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Cyclooxygenase 2: its regulation, role and impact in airway inflammation.

Cyclooxygenase 2: its regulation, role and impact in airway inflammation.

Clin Exp Allergy. 2015 Dec 18;

Authors: Rumzhum NN, Ammit AJ

Abstract
Cyclooxygenase 2 (COX-2: official gene symbol – PTGS2) has long been regarded as playing a pivotal role in the pathogenesis of airway inflammation in respiratory diseases including asthma. COX-2 can be rapidly and robustly expressed in response to a diverse range of pro-inflammatory cytokines and mediators. Thus, increased levels of COX-2 protein and prostanoid metabolites serve as key contributors to pathobiology in respiratory diseases typified by dysregulated inflammation. But COX-2 products may not be all bad: prostanoids can exert anti-inflammatory/bronchoprotective functions in airways in addition to their pro-inflammatory actions. Herein we outline COX-2 regulation and review the diverse stimuli known to induce COX-2 in the context of airway inflammation. We discuss some of the positive and negative effects that COX-2/prostanoids can exert in in vitro and in vivo models of airway inflammation, and suggest that inhibiting COX-2 expression to repress airway inflammation may be too blunt an approach; because although it might reduce the unwanted effects of COX-2 activation, it may also negate the positive effects. Evidence suggests that prostanoids produced via COX-2 upregulation show diverse actions (and herein we focus on prostaglandin E2 as a key example); these can be either beneficial or deleterious and their impact on respiratory disease can be dictated by local concentration and specific interaction with individual receptors. We propose that understanding the regulation of COX-2 expression and associated receptor-mediated functional outcomes may reveal number of critical steps amenable to pharmacological intervention. These may prove invaluable in our quest towards future development of novel anti-inflammatory pharmacotherapeutic strategies for the treatment of airway diseases. This article is protected by copyright. All rights reserved.

PMID: 26685098 [PubMed – as supplied by publisher]

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Regulation of cough by neuronal Na(+)-K(+) ATPases.

Regulation of cough by neuronal Na(+)-K(+) ATPases.

Curr Opin Pharmacol. 2015 Jun 2;22:140-145

Authors: Canning BJ, Farmer DG

Abstract
The Na(+)-K(+) ATPases play an essential role in establishing the sodium gradients in excitable cells. Multiple isoforms of the sodium pumps have been identified, with tissue and cell specific expression patterns. Because the vagal afferent nerves regulating cough must be activated at sustained high frequencies of action potential patterning to achieve cough initiation thresholds, it is a certainty that sodium pump function is essential to maintaining cough reflex sensitivities in health and in disease. The mechanisms by which Na(+)-K(+) ATPases regulate bronchopulmonary vagal afferent nerve excitability are reviewed as are potential therapeutic strategies targeting the sodium pumps in cough.

PMID: 26048736 [PubMed – as supplied by publisher]

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Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions.

Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions.

Pharmacol Rev. 2013;65(2):670-709

Authors: Schmidt M, Dekker FJ, Maarsingh H

Abstract
Since the discovery nearly 60 years ago, cAMP is envisioned as one of the most universal and versatile second messengers. The tremendous feature of cAMP to tightly control highly diverse physiologic processes, including calcium homeostasis, metabolism, secretion, muscle contraction, cell fate, and gene transcription, is reflected by the award of five Nobel prizes. The discovery of Epac (exchange protein directly activated by cAMP) has ignited a new surge of cAMP-related research and has depicted novel cAMP properties independent of protein kinase A and cyclic nucleotide-gated channels. The multidomain architecture of Epac determines its activity state and allows cell-type specific protein-protein and protein-lipid interactions that control fine-tuning of pivotal biologic responses through the “old” second messenger cAMP. Compartmentalization of cAMP in space and time, maintained by A-kinase anchoring proteins, phosphodiesterases, and ?-arrestins, contributes to the Epac signalosome of small GTPases, phospholipases, mitogen- and lipid-activated kinases, and transcription factors. These novel cAMP sensors seem to implement certain unexpected signaling properties of cAMP and thereby to permit delicate adaptations of biologic responses. Agonists and antagonists selective for Epac are developed and will support further studies on the biologic net outcome of the activation of Epac. This will increase our current knowledge on the pathophysiology of devastating diseases, such as diabetes, cognitive impairment, renal and heart failure, (pulmonary) hypertension, asthma, and chronic obstructive pulmonary disease. Further insights into the cAMP dynamics executed by the Epac signalosome will help to optimize the pharmacological treatment of these diseases.

PMID: 23447132 [PubMed – as supplied by publisher]

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SHP-1 Regulation of Mast Cell Function in Allergic Inflammation and Anaphylaxis.

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SHP-1 Regulation of Mast Cell Function in Allergic Inflammation and Anaphylaxis.

PLoS One. 2013;8(2):e55763

Authors: Zhou L, Oh SY, Zhou Y, Yuan B, Wu F, Oh MH, Wang Y, Takemoto C, Van Rooijen N, Zheng T, Zhu Z

Abstract
Allergic inflammation and severe allergic reactions (anaphylaxis) are important in allergen induced diseases. Bacterial products such as lipopolysaccharide (LPS) are ubiquitous and can facilitate allergen induced Th2 immune responses. Phosphatase SHP-1 is critical in regulating immunological homeostasis and in allergen induced Th2 immune responses in the lung. However, the mechanisms underlying the initiation of allergic inflammation and allergen induced anaphylaxis are still not completely elucidated and it is unclear whether SHP-1 plays any role in LPS-induced airway inflammation and in allergen-induced anaphylaxis. In this study we tested the hypothesis that phosphatase SHP-1 plays an important role in allergic inflammation and anaphylaxis and determined whether its effects are through regulation of mast cell functions. SHP-1 deficient (mev/+ and mev/mev) and mast cell deficient (Kit(W-sh)) mice were examined in their responses to LPS airway stimulation and to ovalbumin (OVA) allergen induced systemic anaphylaxis. Compared to wild type mice, mev/+ mice had significantly enhanced LPS induced airway inflammation and OVA induced anaphylactic responses, including hypothermia and clinical symptoms. These changes were mast cell dependent as Kit(W-sh) mice had reduced responses whereas adoptive transfer of mast cells restored the responses. However, T and B cells were not involved and macrophages did not play a significant role in LPS induced airway inflammation. Interestingly, basophil differentiation from SHP-1 deficient bone marrow cells was significantly reduced. These findings provided evidence that through regulation of mast cell functions SHP-1 plays a critical role as a negative regulator in allergic inflammation and in allergen induced anaphylaxis. In addition, SHP-1 seems to be required for normal basophil development.

PMID: 23390550 [PubMed – in process]

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Epithelial regulation of eicosanoid production in asthma.

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Epithelial regulation of eicosanoid production in asthma.

Pulm Pharmacol Ther. 2012 Dec;25(6):432-7

Authors: Hallstrand TS, Lai Y, Henderson WR, Altemeier WA, Gelb MH

Abstract
Alterations in the airway epithelium have been associated with the development of asthma in elite athletes and in subjects that are susceptible to exercise-induced bronchoconstriction (EIB). The syndrome of EIB refers to acute airflow obstruction that is triggered by a period of physical exertion. Asthmatics who are susceptible to EIB have increased levels of cysteinyl leukotrienes (CysLTs, i.e., LTs C?, D?, and E?) in induced sputum and exhaled breath condensate, and greater shedding of epithelial cells into the airway lumen. Exercise challenge in individuals susceptible to this disorder initiates a sustained increase in CysLTs in the airways, and secreted mucin release and smooth muscle constriction, which may be mediated in part through activation of sensory nerves. We have identified a secreted phospholipase A? (sPLA?) with increased levels in the airways of patients with EIB called sPLA? group X(sPLA?-X).We have found that sPLA?-X is strongly expressed in the airway epithelium in asthma. Further,we discovered that transglutaminase 2 (TGM2) is expressed at increased levels in asthma and serves asa regulator of sPLA?-X. Finally, we demonstrated that sPLA?-X acts on target cells such as eosinophils to initiate cellular eicosanoid synthesis. Collectively, these studies identify a novel mechanism linking the airway epithelium to the production of inflammatory eicosanoids by leukocytes.

PMID: 23323271 [PubMed – in process]

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Virginia legislators seek to link health impacts, regulation of power providers – Washington Post

Virginia legislators seek to link health impacts, regulation of power providers
Washington Post
They'll be joined by an asthma sufferer. The two say Virginia's electric utilities generate pollution that causes a range of illnesses costing the state and leading to premature deaths. They'll illustrate the problem with a map showing areas hardest …

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