What can naturally occurring mutations tell us about the pathogenesis of COPD?

Abstract

The airway and emphysema phenotypes of chronic obstructive pulmonary disease (COPD) cluster in susceptible families. Some of this clustering is likely to be the result of shared genetic factors. There are a number of relatively rare syndromes that predispose to COPD, and a growing number of association and linkage studies that have assessed the genetic factors that predispose smokers to airflow obstruction. A review of the literature was performed to determine what has been learnt about the factors and pathways that predispose some individuals to progressive airflow obstruction while others are relatively resistant. There is very strong evidence that the integrity of the extracellular matrix, and in particular the elastin fibres, are important in the pathogenesis of COPD. There is also support for the role of proteinaseantiproteinase imbalance and probably oxidative stress.

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

“…Anti-1-antitrypsin is a protease inhibitor that is important in maintaining the lung parenchymal integrity. Insight into the role of this protease inhibitor in COPD has led to the hypothesis that an imbalance between ECM degrading enzymes and proteins that oppose this activity underlies the early development of emphysema (Gooptu et al, 2009;Marciniak and Lomas, 2009). Polymorphisms in other genes that are involved in ECM homeostasis as well as genes that are involved in the production of detoxifying enzymes such as glutathione transferase, heme oxygenase 1, superoxide dismutase, and possibly others are also likely to be involved in the COPD disease pathology (Marciniak and Lomas, 2009).…”

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

“…atherosclerosis (type I and III collagens, titin and versican) 217 . various fibrotic diseases including liver (type I, III, IV, V, VI collagens and biglycan), [59][60][61]144,196,197,199,200,218 lung (elastin, type I, III, and V collagen), 74,[220][221][222][223][224][225][226][227][228][229][230][231][232] and kidney. 233 Key lessons on the importance of the structural components of the matrix may be harvested from the genetic mutations that lead to pathologies.…”

Bronchiolar Progenitor Cells

“…The observation among cigarette smokers with COPD that clinical measures of severity do not always correlate with the extent of exposure suggests that initiation and/or progression of pathologic changes to the lung may be exacerbated when coupled with other intrinsic and/or environmental factors (1)(2)(3). From an evolutionary and population-based perspective there is a sufficiently broad spectrum of initial responses to lung injury resulting from cigarette smoking that a subpopulation whose genetic composition is poorly suited to appropriately repair damaged tissue progresses to clinical disease.…”