Keratin 8 mutations in transgenic mice predispose to lung injury.

Keratin 8 (K8) is the cytoskeletal intermediate filament protein of simple-type epithelia. Mutations in K8 predispose the affected individual and transgenic mouse to liver disease. However, its role in lung has not been reported in mutant transgenic mouse models. Here, we investigated the susceptibility of two different transgenic mice expressing K8 gly-62-cys or ser-74-ala to lung injury. The mutant transgenic mice were highly susceptible to two independent acute and chronic lung injuries as compared with control mice. Both K8 gly-62-cys mice and K8 ser-74-ala mice showed the markedly enhanced mouse lethality (∼74% mutant mice vs. ∼34% control mice) and more severe lung damage with increased inflammation and apoptosis under L-arginine-mediated acute lung injury. Moreover, the K8 ser-74-ala mice had more severe lung damage with extensive hemorrhage and prominent fibrosis under bleomycin-induced chronic lung injury. Our study provides first direct evidence that the K8 mutations predispose to lung injury in transgenic mice.