title: Epithelial cell apoptosis causes acute lung injury masquerading as emphysema.
abstract: Theories of emphysema traditionally revolved around proteolytic destruction of extracellular matrix. Models have recently been developed that show airspace enlargement with the induction of pulmonary cell apoptosis. The purpose of this study was to determine the mechanism by which a model of epithelial cell apoptosis caused airspace enlargement. Mice were treated with either intratracheal microcystin (MC) to induce apoptosis, intratracheal porcine pancreatic elastase (PPE), or their respective vehicles. Mice from all groups were inflated and morphometry was measured at various time points. Physiology measurements were performed for airway resistance, tissue elastance, and lung volumes. The groups were further analyzed by air-saline quasistatic measurements, surfactant staining, and surfactant functional studies. Mice treated with MC showed evidence of reversible airspace enlargement. In contrast, PPE-treated mice showed irreversible airspace enlargement. The airspace enlargement in MC-treated mice was associated with an increase in elastic recoil due to an increase in alveolar surface tension. PPE-treated mice showed a loss of lung elastic recoil and normal alveolar surface tension, a pattern more consistent with human emphysema. Airspace enlargement that occurs with the MC model of pulmonary epithelial cell apoptosis displays physiology distinct from human emphysema. Reversibility, restrictive physiology due to changes in surface tension, and alveolar enlargement associated with heterogeneous alveolar collapse are most consistent with a mild acute lung injury. Inflation near total lung capacity gives the appearance of enlarged alveoli as neighboring collapsed alveoli exert tethering forces.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Majd
authors.initials: M
authors.lastname: Mouded
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Egea
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Shane M
authors.initials: SM
authors.lastname: Hanlon
authors.forename: A McGarry
authors.initials: AM
authors.lastname: Houghton
authors.forename: Larry W
authors.initials: LW
authors.lastname: Tsai
authors.forename: Edward P
authors.initials: EP
authors.lastname: Ingenito
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000403:Airway Resistance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D004548:Elasticity; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D008176:Lung Volume Measurements; D051379:Mice; D008810:Mice, Inbred C57BL; D052998:Microcystins / Q000633:toxicity; D008954:Models, Biological; D010196:Pancreatic Elastase / Q000633:toxicity; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000175:diagnosis / Q000209:etiology*; D011663:Pulmonary Surfactants; D013500:Surface Tension; D014109:Total Lung Capacity
chemical_list: D052998:Microcystins; D011663:Pulmonary Surfactants; C078588:microcystin; D010196:Pancreatic Elastase