Van Eerdewegh P, Little RD, Dupuis J, et al Nature 2002;418:426–430 

To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma

Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma

A genetic linkage analysis was performed for current asthma and BHR Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma Novel genes of interest were …

Association of the adam33 gene with asthma and bronchial hyperresponsiveness

The adoption of the concept that asthma is primarily a disease most frequently associated with elaboration of T-helper 2 (Th2)-type inflammation has led to the widely held concept that its origins, exacerbation, and persistence are allergen driven. Taking aside the asthma that is expressed in non-allergic individuals leaves the great proportion of asthma that is associated with allergy (or atopy) and that often has its onset in early childhood. Evidence is presented that asthma is primarily an epithelial disorder and that its origin as well as its clinical manifestations have more to do with altered epithelial physical and functional barrier properties than being purely linked to allergic pathways. In genetically susceptible individuals, impaired epithelial barrier function renders the airways vulnerable to early life virus infection, and this in turn provides the stimulus to prime immature dendritic cells toward directing a Th2 response and local allergen sensitization. Continued epithelial susceptibility to environmental insults such as viral, allergen, and pollutant exposure and impaired repair responses leads to asthma persistence and provides the mediator and growth factor microenvironment for persistence of inflammation and airway wall remodeling. Increased deposition of matrix in the epithelial lamina reticularis provides evidence for ongoing epithelial barrier dysfunction, while physical distortion of the epithelium consequent upon repeated bronchoconstriction provides additional stimuli for remodeling. This latter response initially serves a protective function but, if exaggerated, may lead to fixed airflow obstruction associated with more severe and chronic disease. Dual pathways in the origins, persistence, and progression of asthma help explain why anti-inflammatory treatments fail to influence the natural history of asthma in childhood and only partially does so in chronic severe disease. Positioning the airway epithelium as fundamental to the origins and persistence of asthma provides a rationale for pursuit of therapeutics that increase the resistance of the airways to environmental insults rather than concentrating all effort on suppressing inflammation.

The sentinel role of the airway epithelium in asthma pathogenesis

Animal models have been developed to investigate specific components of asthmatic airway inflammation, hyper-responsiveness or remodelling. However, all of these aspects are rarely observed in the same animal. Heaves is a naturally occurring disease of horses that combines these features. It is characterized by stable dust-induced inflammation, bronchospasm and remodelling. The evaluation of horses during well-controlled natural antigen exposure and avoidance in experimental settings allows the study of disease mechanisms in the asymptomatic and symptomatic stages, an approach rarely feasible in humans. Also, the disease can be followed over several years to observe the cumulative effect of repeated episodes of clinical exacerbation or to evaluate long-term treatment, contrasting most murine asthma models. This model has shown complex gene and environment interactions, the involvement of both innate and adaptive responses to inflammation, and the contribution of bronchospasm and tissue remodelling to airway obstruction, all occurring in a natural setting. Similarities with the human asthmatic airways are well described and the model is currently being used to evaluate airway remodelling and its reversibility in ways that are not possible in people for ethical reasons. Tools including antibodies, recombinant proteins or gene arrays, as well as methods for sampling tissues and assessing lung function in the horse are constantly evolving to facilitate the study of this animal model. Research perspectives that can be relevant to asthma include the role of neutrophils in airway inflammation and their response to corticosteroids, systemic response to pulmonary inflammation, and maintaining athletic capacities with early intervention.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1843.2011.02033.x

Heaves, an asthma-like disease of horses.

Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004;126:96S−104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development...

Asthma and Chronic Obstructive Pulmonary Disease Common Genes, Common Environments?

Acute and chronic lung inflammation is driven and controlled by several endogenous mediators that undergo proteolytic conversion from surface-expressed proteins to soluble variants by a disintegrin and metalloproteinase (ADAM)-family members. TNF and epidermal growth factor receptor ligands are just some of the many substrates by which these proteases regulate inflammatory or regenerative processes in the lung. ADAM10 and ADAM17 are the most prominent members of this protease family. They are constitutively expressed in most lung cells and, as recent research has shown, are the pivotal shedding enzymes mediating acute lung inflammation in a cell-specific manner. ADAM17 promotes endothelial and epithelial permeability, transendothelial leukocyte migration, and inflammatory mediator production by smooth muscle and epithelial cells. ADAM10 is critical for leukocyte migration and alveolar leukocyte recruitment. ADAM10 also promotes allergic asthma by driving B cell responses. Additionally, ADAM10 acts as a receptor for Staphylococcus aureus (S. aureus) α-toxin and is crucial for bacterial virulence. ADAM8, ADAM9, ADAM15, and ADAM33 are upregulated during acute or chronic lung inflammation, and recent functional or genetic analyses have linked them to disease development. Pharmacological inhibitors that allow us to locally or systemically target and differentiate ADAM-family members in the lung suppress acute and asthmatic inflammatory responses and S. aureus virulence. These promising results encourage further research to develop therapeutic strategies based on selected ADAMs. These studies need also to address the role of the ADAMs in repair and regeneration in the lung to identify further therapeutic opportunities and possible side effects.

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Background A disintegrin and metalloprotease (ADAM) –33 is a susceptibility gene for asthma and chronic obstructive pulmonary disease whose function remains unknown. Objective Because asthmatic bronchoalveolar lavage fluid contains high levels of soluble ADAM33 (sADAM33), which includes the catalytic domain, we postulated that its release from cell membranes might play functional roles in airway remodeling by promoting angiogenesis. Methods The proangiogenic activity of the highly purified catalytic domain of ADAM33 or a catalytically inactive mutant was studied in vitro (Matrigel assay), ex vivo (human embryonic/fetal lung explants) and in vivo (chorioallantoic membrane assay). The regulation of sADAM33 release from cells overexpressing full-length ADAM33 and its biological activity were characterized. Results We show that the purified catalytic domain of ADAM33, but not its inactive mutant, causes rapid induction of endothelial cell differentiation in vitro, and neovascularization ex vivo and in vivo . We also show that TGF-β 2 enhances sADAM33 release from cells overexpressing full-length ADAM33 and that this truncated form is biologically active. Conclusion The discovery that sADAM33 promotes angiogenesis defines it as a tissue remodeling gene with potential to affect airflow obstruction and lung function independently of inflammation. As TGF-β 2 enhances sADAM33 release, environmental factors that cause epithelial damage may synergize with ADAM33 in asthma pathogenesis, resulting in a disease-related gain of function. This highlights the potential for interplay between genetic and environmental factors in this complex disease.

The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: Implications for airway remodeling in asthma

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The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: Implications for airway remodeling in asthma