title: Complex integration of matrix, oxidative stress, and apoptosis in genetic emphysema.
abstract: Alveolar enlargement, which is characteristic of bronchopulmonary dysplasia, congenital matrix disorders, and cigarette smoke-induced emphysema, is thought to result from enhanced inflammation and ensuing excessive matrix proteolysis. Although there is recent evidence that cell death and oxidative stress punctuate these diseases, the mechanistic link between abnormal lung extracellular matrix and alveolar enlargement is lacking. We hypothesized that the tight-skin (TSK) mouse, which harbors a spontaneous internal duplication in the microfibrillar glycoprotein fibrillin-1, might show whether matrix alterations are sufficient to promote oxidative stress and cell death, injury cascades central to the development of clinical emphysema. We observed no evidence of increased metalloprotease activation by histochemical and zymographic methods. We did find initial oxidative stress followed by increased apoptosis in the postnatal TSK lung. Both blunted antioxidant production and reduced extracellular superoxide dismutase activity were evident in the neonatal lung. High-dose antioxidant treatment with N-acetylcysteine improved airspace caliber and attenuated oxidative stress and apoptosis in neonatal and adult TSK mice. These data establish that an abnormal extracellular matrix without overt elastolysis is sufficient to confer susceptibility to postnatal normoxia, reminiscent of bronchopulmonary dysplasia. The resultant oxidative stress and apoptosis culminate in profound airspace enlargement. The TSK lung exemplifies the critical interplay between extracellular matrix, oxidative stress, and cell-death cascades that may contribute to genetic and acquired airspace enlargement.
authors: Divisionsof Pulmonary, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. eneptune@jhmi.edu
authors: Megan
authors: M
authors: Podowski
authors: Carla L
authors: CL
authors: Calvi
authors: Christopher
authors: C
authors: Cheadle
authors: Rubin M
authors: RM
authors: Tuder
authors: Shyam
authors: S
authors: Biswals
authors: Enid R
authors: ER
authors: Neptune
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology*; D011656:Pulmonary Emphysema / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D054392:Adipokines
chemical_list: D000975:Antioxidants; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines