Lung development and susceptibility to chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, because only a proportion ( approximately 15%) of smokers develop chronic obstructive pulmonary disease with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes, either by null mutation, hypomorphism, or gain or loss of function, results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early-onset emphysema if the effect is milder. Likewise, null mutants that interfere with matrix assembly and/or integrity, such as elastin, lysyl oxidase, or fibrillin, also result in alveolar dysplasia. Importantly, null mutation of Smad3, which encodes a receptor-activated Smad in the transforming growth factor-beta signaling pathway, results in a more subtle failure to correctly organize the alveolar matrix, which is in turn antecedent to early-onset emphysema mediated by matrix metalloproteinase-9. Furthermore, exposure to side-stream smoke profoundly exacerbates and accelerates alveolar destruction, leading to more severe early-onset emphysema in young Smad3-null mice (unpublished data). Interestingly, polymorphisms in the fibrillin, transforming growth factor-beta type II receptor, and matrix metalloproteinase-9 genes have been described in humans with emphysema. Thus, dysplastic or degraded matrix cannot provide the structural niche for alveolar stem/progenitor cells to assume the correct phenotype and/or repair the alveolar cell lineage niche. The hope is that providing the correct exogenous signals can coax them into doing so.
Warburton
David
D
Saban Research Institute Children's Hospital-Los Angeles, 4650 Sunset Blvd. #35, Los Angeles, CA 90027, USA. dwarburton@chla.usc.edu
Gauldie
Jack
J
Bellusci
Saverio
S
Shi
Wei
W
D000367:Age Factors; D000818:Animals; D004330:Drosophila / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000196:embryology*; D006801:Humans; D008168:Lung / Q000196:embryology / Q000473:pathology / Q000503:physiopathology*; D045726:Metalloproteases / Q000502:physiology; D051379:Mice; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000196:embryology / Q000235:genetics / Q000503:physiopathology*; D012907:Smoking / Q000009:adverse effects
D045726:Metalloproteases