Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema.
Cigarette smoking is the strongest risk factor for emphysema. However, sensitivity to cigarette smoke-induced emphysema is highly variable, and numerous genetic and environmental factors are thought to mitigate lung response to injury. We report that the quantity of functional elastin in the lung is an important modifier of both lung development and response to injury. In mice with low levels of elastin, lung development is adversely affected, and mice manifest with congenital emphysema. Animals with intermediate elastin levels exhibit normal alveolar structure but develop worse emphysema than normal mice following cigarette smoke exposure. Mechanical testing demonstrates that lungs with low levels of elastin experience greater tissue strains for any given tissue stress compared with wild-type lungs, implying that force-mediated propagation of lung injury through alveolar wall failure may worsen the emphysema after an initial enzymatic insult. Our findings suggest that quantitative deficiencies in elastin predispose to smoke-induce emphysema in animal models and suggest that humans with altered levels of functional elastin could have relatively normal lung function while being more susceptible to smoke-induced lung injury.
Shifren
Adrian
A
Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA.
Durmowicz
Anthony G
AG
Knutsen
Russell H
RH
Hirano
Eiichi
E
Mecham
Robert P
RP
D000818:Animals; D004195:Disease Models, Animal; D004549:Elastin / Q000235:genetics / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D012906:Smoke / Q000009:adverse effects*
D012906:Smoke; D004549:Elastin