title: Role of repeated lung injury and genetic background in bleomycin-induced fibrosis.
abstract: Current hypotheses of the pathogenesis of many forms of pulmonary fibrosis suggest that (i) a stimulus results in repeated or prolonged episodes of lung injury, and (ii) genetic factors modulate the outcome of the injury. The commonly employed single-exposure bleomycin model results in only temporary fibrosis. Therefore, we evaluated whether repeated bleomycin exposures, in the setting of a genetic background more likely to develop a T helper 2 (Th2) response, would induce prolonged fibrosis. Lung fibrosis was induced by intratracheal bleomycin injection, either as a single exposure or as three consecutive exposures. We found that bleomycin induced a Th2-like environment in both Th1-biased C57BL/6J and Th2-biased DBA/2 mice. We also found histologic changes and collagen increases consistent with lung injury/fibrosis at early time points, but prolonged fibrosis only after multiple exposures in the Th2-biased DBA/2 mice. We also determined if impaired healing of bleomycin-induced injury would prolong fibrosis in the C57BL/6J mice. Endothelial nitric oxide (which protects endothelial cells from oxidant-induced injury) synthase knockout animals on a C57BL/6J background also had prolonged fibrosis, similar to DBA/2 mice, after multiple bleomycin exposures. This was specific to eNOS, as inducible nitric oxide synthase knockout animals cleared the fibrosis as effectively as wild-type C57BL/6J mice. This data indicate that healing of injury/fibrosis after bleomycin is complex and can be determined by a number of genetic and environmental factors.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.
authors.forename: Man Pyo
authors.initials: MP
authors.lastname: Chung
authors.forename: Martha M
authors.initials: MM
authors.lastname: Monick
authors.forename: Nabeel Y
authors.initials: NY
authors.lastname: Hamzeh
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.forename: Gary W
authors.initials: GW
authors.lastname: Hunninghake
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000378:metabolism / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced* / Q000235:genetics*; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D018793:Interleukin-13; D012333:RNA, Messenger; D001761:Bleomycin; D012313:RNA; D007371:Interferon-gamma; D003094:Collagen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse