Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin.
Because mouse strains susceptible to bleomycin, such as C57BL/ 6J, tend to produce T helper type 1 (Th1) cytokines in response to immune activation, we hypothesized that the inflammatory response to bleomycin is mediated, in part, by local production of the Th1 cytokine interferon-gamma (IFN-gamma). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN-gamma protein (by enzyme-linked immunosorbent assay) in bronchoalveolar lavage fluid at 24 h, and subsequently increased lung inflammation, weight loss, and mortality 10 d after intratracheal bleomycin administration compared with fibrosis-resistant BALB/c mice or saline control mice. To directly determine a role for IFN-gamma in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN-gamma gene (IFN-gamma[-/-]) and wild-type C57BL/6J mice to intratracheal bleomycin. IFN-gamma(-/-) mice demonstrated significantly lower parenchymal inflammation, weight loss, and mortality 10 d after 5 U/kg intratracheal bleomycin administration compared with control mice. At 3 wk after 1.5 U/kg bleomycin exposure, single lung collagen determined by hydroxyproline assay was significantly lower in IFN-gamma(-/-) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN-gamma mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.
Chen
E S
ES
Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
Greenlee
B M
BM
Wills-Karp
M
M
Moller
D R
DR
D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007322:Instillation, Drug; D007371:Interferon-gamma / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D015847:Interleukin-4 / Q000032:analysis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D015996:Survival Rate; D014132:Trachea
D016207:Cytokines; D012333:RNA, Messenger; D001761:Bleomycin; D015847:Interleukin-4; D007371:Interferon-gamma; D003094:Collagen