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BBA - General Subjects (v.1810, #11)

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Biochemistry of asthma by Loretta G. Que; Yvonne Janssen-Heininger (pp. 1007-1007).

Nitric oxide metabolism in asthma pathophysiology by Sudakshina Ghosh; Serpil C. Erzurum (pp. 1008-1016).

Asthma, a chronic inflammatory disease is typically characterized by bronchoconstriction and airway hyper-reactivity.A wealth of studies applying chemistry, molecular and cell biology to animal model systems and human asthma over the last decade has revealed that asthma is associated with increased synthesis of the gaseous molecule nitric oxide (NO).The high NO levels in the oxidative environment of the asthmatic airway lead to greater formation of reactive nitrogen species (RNS) and subsequent oxidation and nitration of proteins, which adversely affect protein functions that are biologically relevant to chronic inflammation. In contrast to the high levels of NO and nitrated products, there are lower levels of beneficial S-nitrosothiols (RSNO), which mediate bronchodilation, due to greater enzymatic catabolism of RSNO in the asthmatic airways.This review discusses the rapidly accruing data linking metabolic products of NO as critical determinants in the chronic inflammation and airway reactivity of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.► Asthma is an inflammatory disease characterized by altered NO metabolism. ► Greater NO synthesis in asthma is accompanied by more nitration and less nitrosylation of airway-proteins. ► Greater protein nitration is associated with adverse effects on protein functions. ► Loss of S-nitrosothiol (SNO) products leads to loss of bronchodilator effects. ► Abnormal NO metabolism contributes to defining features of asthma.

Keywords: Nitric oxide; Asthma; Nitrative stress; Nitration; S-nitrosylation

The biochemistry of asthma by Benjamin Gaston (pp. 1017-1024).

Asthma is not one disease. Different patients have biochemically distinct phenotypes.Biomarker analysis was developed to identify inflammation in the asthmatic airway. It has led to a renewed interest in biochemical abnormalities in the asthmatic airway. The biochemical determinants of asthma heterogeneity are many. Examples include decreased activity of superoxide dismutases; increased activity of eosinophil peroxidase, S-nitrosoglutathione reductase, and arginases; decreased airway pH; and increased levels of asymmetric dimethyl arginine.New discoveries suggest that biomarkers such as exhaled nitric oxide reflect complex airway biochemistry. This biochemistry can be informative and therapeutically relevant.Improved understanding of airway biochemistry will lead to new tests to identify biochemically unique subpopulations of patients with asthma. It will also likely lead to new, targeted treatments for these specific asthma subpopulations. This article is part of a Special Issue entitled Biochemistry of Asthma.► Asthma is not one disease: patients have distinct biochemical phenotypes. ► S-Nitrosothiols are relevant NOS products in the asthmatic airways. ► pH is often low in the asthmatic airway and is metabolically regulated. ► Many patients with asthma have decreased SOD activity. ► Asthma biochemistry may inform novel, targeted therapies.

Keywords: Asthma; S-Nitrosoglutathione; pH; Superoxide dismutase

Epithelial, dendritic, and CD4⁺ T cell regulation of and by reactive oxygen and nitrogen species in allergic sensitization by Karina Ckless; Samantha R. Hodgkins; Jennifer L. Ather; Rebecca Martin; Matthew E. Poynter (pp. 1025-1034).

While many of the contributing cell types and mediators of allergic asthma are known, less well understood are the factors that induce allergy in the first place. Amongst the mediators speculated to affect initial allergen sensitization and the development of pathogenic allergic responses to innocuous inhaled antigens and allergens are exogenously or endogenously generated reactive oxygen species (ROS) and reactive nitrogen species (RNS).The interactions between ROS/RNS, dendritic cells (DCs), and CD4⁺ T cells, as well as their modulation by lung epithelium, are of critical importance for the genesis of allergies that later manifest in allergic asthma. Therefore, this review will primarily focus on the initiation of pulmonary allergies and the role that ROS/RNS may play in the steps therein, using examples from our own work on the roles of NO₂ exposure and airway epithelial NF-κB activation.Endogenously generated ROS/RNS and those encountered from environmental sources interact with epithelium, DCs, and CD4⁺ T cells to orchestrate allergic sensitization through modulation of the activities of each of these cell types, which quantitiatively and qualitatively dictate the degree and type of the allergic asthma phenotype.Knowledge of the effects of ROS/RNS at the molecular and cellular levels has the potential to provide powerful insight into the balance between inhalational tolerance (the typical immunologic response to an innocuous inhaled antigen) and allergy, as well as to potentially provide mechanistic targets for the prevention and treatment of asthma.► Reactive oxygen species (ROS) and reactive nitrogen species (RNS) affect allergic sensitization. ► The lung is exposed to environmental and endogenously generated ROS and RNS. ► Epithelial, dendritic, and CD4⁺ T cells are targets and generators of ROS and RNS. ► The NF-kappaB (NF-κB) pathway is an especially important intracellular target of ROS and RNS. ► Airway epithelial NF-κB activity modulates allergic sensitization.

Keywords: Asthma; Epithelium; Dendritic cell; CD4; ⁺; T cell; Reactive oxygen species; Reactive nitrogen species; NF-kappaB

Nox enzymes in allergic airway inflammation by Albert van der Vliet (pp. 1035-1044).

Chronic airway diseases such as asthma are linked to oxidative environmental factors and are associated with increased production of reactive oxygen species (ROS). Therefore, it is commonly assumed that oxidative stress is an important contributing factor to asthma disease pathogenesis and that antioxidant strategies may be useful in the treatment of asthma. A primary source of ROS production in biological systems is NADPH oxidase (NOX), originally associated primarily with inflammatory cells but currently widely appreciated as an important enzyme system in many cell types, with a wide array of functional properties ranging from antimicrobial host defense to immune regulation and cell proliferation, differentiation and apoptosis. Given the complex nature of asthma disease pathology, involving many lung cell types that all express NOX homologs, it is not surprising that the contributions of NOX-derived ROS to various aspects of asthma development and progression are highly diverse and multifactorial. It is the purpose of the present review to summarize the current knowledge with respect to the functional aspects of NOX enzymes in various pulmonary cell types, and to discuss their potential importance in asthma pathogenesis. This article is part of a Special Issue entitled: Biochemistry of Asthma.► NADPH oxidases (NOX) are a primary source of ROS production during chronic inflammation. ► NOX enzymes are critical in host defense, as well as tissue (re)generation and remodeling. ► The contributions of NOX enzymes to asthma pathology are multifactorial. ► Selective targeting of specific NOX enzymes may be useful in treatment of asthma.

Keywords: NADPH oxidase (NOX); Dual oxidase (DUOX); Inflammation; Epithelial cell; Host defense; Remodeling

Glutathione biochemistry in asthma by Niki L. Reynaert (pp. 1045-1051).

Oxidative stress in an important hallmark of asthma and much research has therefore focused on the predominant antioxidant in the lungs, namely the tripeptide glutathione.In lung samples of patients with asthma increased levels of glutathione are typically observed, which appear to relate to the level of pulmonary inflammation and are therefore regarded as an adaptive response to the associated oxidative stress. Also in blood samples increased total GSH levels have been reported, representing the systemic inflammatory component of the disease. In addition, a number of the antioxidant enzymes involved in the maintenance of the GSH/GSSG ratio as well as enzymes that utilize GSH have been found to be altered in the lungs and blood of asthmatics and will be summarized in this review. Very few studies have however linked enzymatic alterations to GSH levels or found that either of these correlated with disease severity. Some animal studies have started to investigate the pathophysiological role of GSH biochemistry in asthma and have yielded surprising results. Important in this respect is the physiological role of the GSH redox equilibrium in determining the outcome of immune responses, which could be deregulated in asthmatics and contribute to the disease.Clinical data as well as animal and cell culture studies regarding these aspects of GSH in the context of asthma will be summarized and discussed in this review. This article is part of a Special Issue entitled: Biochemistry of Asthma.►Glutathione levels are increased in lungs and blood of patients with asthma. ►This can be seen as part of the adaptive response to oxidative stress. ►Most enzymes involved in maintaining reduced glutathione are altered. ►However, glutathione and enzyme levels are rarely examined in conjunction. ►Interesting new studies on the influence of glutathione redox homeostasis on immune responses.

Keywords: Glutathione; Asthma; Oxidative stress; Redox balance; Glutathione peroxidase; Glutathione reductase; Glutathione-S-transferase; Glutaredoxin

Emerging pathways in asthma: Innate and adaptive interactions by Ko-Wei Lin; Jinghong Li; Patricia W. Finn (pp. 1052-1058).

Allergic asthma is a complex and chronic airway inflammatory disorder, and the prevalence of asthma has increased. Adaptive antigen-dependent immunity is a classical pathway of asthmatic pathology. Recent studies have focused on innate antigen-independent immunity in asthma.This review discusses updated research associating innate immunity with allergic asthma. We focus on innate molecules (Toll-like receptors and nucleotide-binding oligomerization domain-like receptors) and review studies regarding innate and adaptive interactions in allergic responses (surfactant protein D, lipopolysaccharide, and early life immune responses). We also highlight new emerging concepts in the field applicable to innate immunity and asthma.Innate immunity plays a key role in asthma. Understanding innate and adaptive interactions provide significant information in asthmatic research. Innate molecules not only contribute to classical pulmonary defense, but also modulate inflammatory responses. Emerging concepts in the analysis of the microbiome, microRNA and autophagy may provide new insights in searching therapeutic targets.Finding specific mechanisms of innate and/or adaptive immunity in asthma are timely goals for further research. Integration of bioinformatics and systems biology tools, particularly in relation to microbiome analysis, may be helpful in providing an understanding to allergic immune responses. This article is part of a Special Issue entitled Biochemistry of Asthma.► Provides an overview of adaptive and innate immunity in allergic responses. ► Reviews important innate molecules (TLRs and NLRs) in allergic asthma. ► Reviews studies of innate and adaptive interactions in allergic responses. ► Reviews emerging concepts including microbiome, microRNA, and autophagy.

Keywords: Lung; Asthma; Airway inflammation; Innate

Proteinases as molecular adjuvants in allergic airway disease by Paul C. Porter; Tianshu Yang; Amber Luong; George L. Delclos; Stuart L. Abramson; Farrah Kheradmand; David B. Corry (pp. 1059-1065).

Asthma and related respiratory tract allergic diseases are among the most common chronic diseases of adults and children. Despite their importance, disease course cannot be predicted and treatment remains non-specific and potentially hazardous, with no means for cure. Improved clinical management of asthma will require an improved understanding of the fundamental factors that initiate allergic inflammation, especially T helper type 2 (T_H2) cell induction.In this review, we explore the Proteinase Hypothesis of allergic airway disease, considering specifically how organismal proteinases contribute to the expression of allergic disease and potentially important proteinase signaling pathways.Proteinases from diverse sources (bacteria, fungi, plants) may cause occupational asthma by acting as immune adjuvant factors that specifically elicit T_H2 cell-dependent allergic inflammation. However, more conventional allergic airway diseases (asthma, allergic sinusitis) are more likely to arise from contained fungal or viral infections of the airway in which proteinases are produced and serve as major virulence factors. Proteinases may elicit allergic disease by disrupting numerous cellular proteins, potentially including Toll like receptor (TLR) 4, but critical proteinase-activated signaling pathways remain largely unknown.Clarification of how proteinases cause allergic disease, specifically confirming an infectious basis for airway proteinase exposure, will likely radically advance how asthma and related respiratory tract disorders are diagnosed and treated. This article is part of a Special Issue entitled Biochemistry of Asthma.► Proteinases are now recognized as important allergic disease virulence factors. ► Fungi and viruses are potentially important sources of allergenic proteinases. ► Proteinase-activated signaling mechanisms are poorly understood. ► Management of allergic disease will improve with clarification of proteinase biology.

Keywords: Asthma; Allergic airway disease; Allergic fungal rhinosinusitis (AFRS); Allergic bronchopulmonary aspergillosis (ABPA); Proteinase; T helper cell type 2

T_H17 cells in asthma and inflammation by Shean J. Aujla; John F. Alcorn (pp. 1066-1079).

The chronic airway disease asthma causes significant burden to patients as well as the healthcare system with limited options for prevention or cure. Inadequate treatment strategies are most likely due to the complex heterogeneous nature of asthma. Furthermore, the severe asthma phenotype is characterized by the lack of a response to standard medication, namely, corticosteroids.In the last several years it has been shown that the eosinophilic/atopic phenotype of asthma driven by T_H2 mechanisms is not the only immunologic pathway contributing to disease. In fact, there has been evidence revealing that severe asthmatics in particular have neutrophilic inflammation, and this is associated with corticosteroid resistance. T_H17 cells, a recently discovered lineage of T helper cells, play an important role in lung host defense against multiple pathogens via production of the cytokine IL‐17. IL‐17 promotes neutrophil production and chemotaxis via multiple factors.Mouse and human studies provide robust evidence that T_H17 cells and IL‐17 play a role in severe asthma and may contribute to corticosteroid resistance.As we learn more about T_H17 cells in severe asthma, the goal is to potentially target this pathway for treatment in the hope of significantly improving the quality of life for those children and adults affected with this disease. This article is part of a Special Issue entitled: Biochemistry of Asthma.► Severe, steroid resistant asthma is often characterized by airway neutrophilia. ► While T_H2 cells drive mild asthma, severe asthma may have a key T_H17 component. ► Asthma models have shown a role for the T_H17/IL‐17 in promoting airway disease. ► T_H17 induced allergic airway disease is steroid resistant in mouse models. ► Human studies show elevated levels of IL‐17 in severe, steroid resistant asthmatics.

Keywords: IL-17; Allergy; Lung

Viruses and asthma by Daniel E. Dulek; R. Stokes Peebles Jr. (pp. 1080-1090).

Viral respiratory infection has long been known to influence the occurrence of asthma exacerbations. Over the last 20years much effort has been put into clarifying the role that viral respiratory infections play in the eventual development of asthma.In this review we give a general background of the role of viruses in the processes of asthma exacerbation and asthma induction. We review recent additions to the literature in the last 3years with particular focus on clinical and epidemiologic investigations of influenza, rhinovirus, bocavirus, respiratory syncytial virus, and metapneumovirus.The development of asthma emerges from a complex interaction of genetic predisposition and environmental factors with viral infection likely playing a significant role in the effect of environment on asthma inception. This article is part of a Special Issue entitled: Biochemistry of Asthma.Further understanding of the role that viruses play in asthma exacerbation and inception will contribute to decreased asthma morbidity in the future. This article is part of a Special Issue entitled: Biochemistry of Asthma.► Viral respiratory tract infection is a significant trigger of asthma exacerbation. ► Human rhinovirus and RSV infections in infancy are associated with asthma inception. ► Newly discovered and emergent viruses may be associated with asthma exacerbation. ► Genetic factors influence asthma inception following infantile RSV infection.

Keywords: Abbreviations; ACIP; Advisory Committee on Immunization practices; HBoV; human bocavirus; RSV; respiratory syncytial virus; ED; emergency department; HMO; health care maintenance organization; CDC; Centers for Disease Control and Prevention; AI/AN; American Indian/Alaska Native; HRV; human rhinovirus; HRVC; human rhinovirus C; OR; odds ratio; NSVN; New Vaccine Surveillance Network; ARI/F; acute respiratory infection or fever; HRVA; human rhinovirus A; HRVB; human rhinovirus B; DFA; direct fluorescent antibody; COAST; Childhood Origins of Asthma Study; ICD-9; International Classification of Diseases-9; AHR; airway hyperreactivity; dsRNA; double stranded RNA; TABS; Tennessee Asthma Bronchiolitis Study; hMPV; human metapneumovirus; LRTI; lower respiratory tract infectionAsthma; Viral infection; Influenza; 2009 H1N1 influenza; Rhinovirus; Bocavirus; Respiratory syncytial virus; Human metapneumovirus

Isoprostanes and asthma by Judith A. Voynow; Apparao Kummarapurugu (pp. 1091-1095).

Isoprostanes are prostaglandin (PG)-like compounds generated in vivo following oxidative stress by non-enzymatic peroxidation of polyunsaturated fatty acids, including arachidonic acid. They are named based on their prostane ring structure and by the localization of hydroxyl groups on the carbon side chain; these structural differences result in a broad array of isoprostane molecules with varying biological properties. Generation of specific isoprostanes is also regulated by host cell redox conditions; reducing conditions favor F₂-isoprostane production while under conditions with deficient antioxidant capacity, D₂- and E₂-isoprostanes are formed. F₂-isoprostanes (F₂-isoP) are considered reliable markers of oxidative stress in pulmonary diseases including asthma. Importantly, F₂-isoP and other isoprostanes function as ligands for PG receptors, and potentially other receptors that have not yet been identified. They have been reported to have important biological properties in many organs. In the lung, isoprostanes regulate cellular processes affecting airway smooth muscle tone, neural secretion, epithelial ion flux, endothelial cell adhesion and permeability, and macrophage adhesion and function. In this review, we will summarize the evidence that F₂-isoP functions as a marker of oxidative stress in asthma, and that F₂-isoP and other isoprostanes exert biological effects that contribute to the pathogenesis of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.► Isoprostanes are non-enzymatic peroxidation products of polyunsaturated fatty acids. ► F2-isoprostane, a stable biomarker of oxidative stress, is increased in asthma. ► Isoprostanes activate receptors to regulate airway and immune functions in asthma.

Keywords: Abbreviations; ARE; antioxidant response element; ASM; airway smooth muscle; COX; Cyclooxygenase; EFS; electrical field stimulation; F; ₂; -isoP; F; ₂; -isoprostanes; GC; Gas chromatography; HDM; House dust mite; ICS; inhaled corticosteroids; LC; liquid chromatography; MS; mass spectrometry; Nrf2; NF-E2 related factor-2; PG; prostaglandin; RIA; radioimmunoassay; EIA; enzyme-linked immunoassay; UPLC; ultraperformance liquid chromatographyIsoprostane; Cyclopentenone; Oxidative stress; Asthma; Airway smooth muscle

Leukotrienes and airway inflammation by Katsuhide Okunishi; Marc Peters-Golden (pp. 1096-1102).

Asthma is a common chronic inflammatory disease of the airways characterized by airway obstruction and hyperresponsiveness. Leukotrienes (LTs) are lipid mediators that contribute to many aspects of asthma pathogenesis. As the LT pathway is relatively steroid-resistant, its blockade by alternative strategies is a desirable component of asthma management. Cysteinyl LT (cysLT) receptor 1 antagonists (LTRAs) have been utilized worldwide for more than 10years, and while their efficacy in asthma is well accepted, their limitations are also evident.In this review, we summarize the biological effects of LTs in asthma, review recent advances in LT receptors, and consider possible new therapeutic targets in the LT pathway that offer the potential to achieve better control of asthma in the future.CysLTs play pathogenetic roles in many aspects of asthma, and blockade of cysLT receptor 1 by currently available LTRAs is certainly beneficial in disease management. On the other hand, the limitations of LTRAs are also apparent. Recent studies have revealed new receptors for cysLTs other than classical cysLT receptors 1 and 2, as well as the potential importance of LTB₄ in asthma.Recent findings provide clues to new approaches for targeting the LT pathway that may overcome the current limitations of LTRAs and achieve superior control of asthma. This article is part of a Special Issue entitled: Biochemistry of Asthma.► CysLTs play pathogenetic roles in many aspects of asthma. ► While efficacious, limitations of LTRAs are also evident. ► Recent studies have revealed new receptors for cysLTs. ► The potential importance of LTB₄ in asthma is also recognized. ► Recent findings provide a basis for new strategies for targeting of the LT pathway.

Keywords: Asthma; Cysteinyl leukotriene; Leukotriene receptor antagonist; 5-Lipoxygenase; Leukotriene B; ₄

Epigenetics of asthma by Andrew L. Durham; Coen Wiegman; Ian M. Adcock (pp. 1103-1109).

Asthma is caused by both heritable and environmental factors. It has become clear that genetic studies do not adequately explain the heritability and susceptibility to asthma. The study of epigenetics, heritable non-coding changes to DNA may help to explain the heritable component of asthma. Additionally, epigenetic modifications can be influenced by the environment, including pollution and cigarette smoking, which are known asthma risk factors. These environmental trigger-induced epigenetic changes may be involved in skewing the immune system towards a Th2 phenotype following in utero exposure and thereby enhancing the risk of asthma. Alternatively, they may directly or indirectly modulate the immune and inflammatory processes in asthmatics via effects on treatment responsiveness. The study of epigenetics may therefore play an important role in our understanding and possible treatment of asthma and other allergic diseases. This article is part of a Special Issue entitled: Biochemistry of Asthma.► Asthma is a major disease of the airways, which has both environmental and heritable components. ► Epigenetics refers to non-coding changes to DNA and/or histones which may explain the heritable component of asthma. ► Epigenetics can be altered by environmental factors such as pollution and smoking. ► This review covers the main mechanisms of epigenetic regulation and how they are altered in asthma.

Keywords: Asthma; Epigenetics; Acetylation; Methylation; Environmental stress

Regulation of mucin secretion and inflammation in asthma: A role for MARCKS protein? by Teresa D. Green; Anne L. Crews; Joungjoa Park; Shijing Fang; Kenneth B. Adler (pp. 1110-1113).

A major characteristic of asthmatic airways is an increase in mucin (the glycoprotein component of mucus) producing and secreting cells, which leads to increased mucin release that further clogs constricted airways and contributes markedly to airway obstruction and, in the most severe cases, to status asthmaticus. Asthmatic airways show both a hyperplasia and metaplasia of goblet cells, mucin-producing cells in the epithelium; hyperplasia refers to enhanced numbers of goblet cells in larger airways, while metaplasia refers to the appearance of these cells in smaller airways where they normally are not seen. With the number of mucin-producing and secreting cells increased, there is a coincident hypersecretion of mucin which characterizes asthma. On a cellular level, a major regulator of airway mucin secretion in both in vitro and in vivo studies has been shown to be MARCKS (myristoylated alanine-rich C kinase substrate) protein, a ubiquitous substrate of protein kinase C (PKC).In this review, properties of MARCKS and how the protein may regulate mucin secretion at a cellular level will be discussed. In addition, the roles of MARCKS in airway inflammation related to both influx of inflammatory cells into the lung and release of granules containing inflammatory mediators by these cells will be explored. This article is part of a Special Issue entitled: Biochemistry of Asthma.► Marcks: structure & membrane binding. ► Mucus, inflammation and asthma: a role for marcks. ► Marcks and inflammation.

Keywords: MARCKS; Mucin; Secretion; Asthma

Biochemical effects of ozone on asthma during postnatal development by Richard L. Auten; W. Michael Foster (pp. 1114-1119).

Ozone exposure during early life has the potential to contribute to the development of asthma as well as to exacerbate underlying allergic asthma.Developmentally regulated aspects of sensitivity to ozone exposure and downstream biochemical and cellular responses.Developmental differences in antioxidant defense responses, respiratory physiology, and vulnerabilities to cellular injury during particular developmental stages all contribute to disparities in the health effects of ozone exposure between children and adults.Ozone exposure has the capacity to affect multiple aspects of the “effector arc” of airway hyperresponsiveness, ranging from initial epithelial damage and neural excitation to neural reprogramming during infancy. This article is part of a Special Issue entitled: Biochemistry of Asthma.► Juvenile ozone exposure responses differ from adult responses. ► Antioxidant defenses / genetically regulated host responses govern the ozone contribution to asthma. ► Lung structural changes after early life ozone exposures may permanently affect airway stability.

Keywords: Airway hyperreactivity; Antioxidant defense; Airway inflammation

Obesity, metabolic dysregulation and oxidative stress in asthma by Njira L. Lugogo; Divya Bappanad; Monica Kraft (pp. 1120-1126).

Epidemiological data demonstrate an increased risk of developing incident asthma with increasing adiposity. While the vast majority of studies support the interaction between obesity and asthma, the causality is unclear.This article will review the current literature supporting the presence of an obese asthma phenotype and the possible mechanisms mediating the effects of obesity on asthma.Obesity is associated with poor asthma control, altered responsiveness to medications and increased morbidity. Obesity is characterized by systemic inflammation that may result in increased airway inflammation. However, this assertion is not supported by current studies that demonstrate a lack of significant airway inflammation in obese asthmatics. In spite this observation one must consider limitations of these studies including the fact that most subjects were treated with inhaled corticosteroids that would likely alter inflammation in the lung. Thus, it remains unclear if obesity is associated with alterations in inflammation in the airways of subjects with asthma.Hormones such as leptin and adiponectin are affected by obesity and may play a role in mediating innate immune responses and allergic responses, respectively. The role of oxidative stress remains controversial and the current evidence suggests that while oxidative stress is important in asthma, it does not fully explain the characteristics associated with this unique phenotype.Obesity related asthma is associated with increased morbidity and differential response to asthma therapies. Understanding the mechanisms mediating this phenotype would have significant implications for millions of people suffering with asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.► We review the literature supporting an obesity asthma phenotype. ► We present an overview of the possible mechanisms mediating obesity related increases in asthma. ► Obesity results in an increased risk of asthma, however, the mechanism is unclear. ► Further studies are required to delineate the mechanisms behind this association and increased understanding would have significant public health implications.

Keywords: Asthma; Obesity; Metabolic syndrome; Oxidative stress; Leptin; Inflammation

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BBA - General Subjects (v.1810, #11)