TY - JOUR
T1 - Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin
AU - Chen, Edward S.
AU - Greenlee, Brian M.
AU - Wills-Karp, Marsha
AU - Moller, David R.
PY - 2001
Y1 - 2001
N2 - 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-γ (IFN-γ). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN-γ 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-γ in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN-γ gene (IFN-γ[-/-]) and wild-type C57BL/6J mice to intratracheal bleomycin. IFN-γ(-/-) 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 lagen determined by hydroxyproline assay was significantly lower in IFN-γ(-/-) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN-γ mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.
AB - 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-γ (IFN-γ). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN-γ 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-γ in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN-γ gene (IFN-γ[-/-]) and wild-type C57BL/6J mice to intratracheal bleomycin. IFN-γ(-/-) 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 lagen determined by hydroxyproline assay was significantly lower in IFN-γ(-/-) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN-γ mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.
UR - http://www.scopus.com/inward/record.url?scp=0035027015&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035027015&partnerID=8YFLogxK
U2 - 10.1165/ajrcmb.24.5.4064
DO - 10.1165/ajrcmb.24.5.4064
M3 - Article
C2 - 11350823
AN - SCOPUS:0035027015
SN - 1044-1549
VL - 24
SP - 545
EP - 555
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 5
ER -