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(American Journal of Pathology. 2005;167:1221-1229.)
© 2005 American Society for Investigative Pathology

Susceptibility of Signal Transducer and Activator of Transcription-1-Deficient Mice to Pulmonary Fibrogenesis

Dianne M. Walters^*, Aurita Antao-Menezes, Jennifer L. Ingram^*, Annette B. Rice^*, Abraham Nyska^*, Yoshiro Tani^*, Steven R. Kleeberger^* and James C. Bonner^*

From the Laboratories of Respiratory Biology and Experimental Pathology,^* National Institute of Environmental Health Sciences, Research Triangle Park; and the Division of Biological Sciences, CIIT Centers for Health Research, Research Triangle Park, North Carolina

The signal transducer and activator of transcription (Stat)-1 mediates growth arrest and apoptosis. We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1^–/–) mice. Two weeks after bleomycin aspiration (3 U/kg), Stat1^–/– mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice. Growth factors [epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)] enhanced [³H]thymidine uptake in lung fibroblasts isolated from Stat1^–/– mice compared to wild-type mice. Interferon (IFN)-, which signals growth arrest via Stat1, inhibited EGF- or PDGF-stimulated mitogenesis in wild-type fibroblasts but enhanced [³H]thymidine uptake in Stat1^–/– fibroblasts. Moreover, IFN- treatment in the absence of growth factors induced a concentration-dependent increase in [³H]thymidine uptake in Stat1^–/– but not wild-type fibroblasts. Mitogen-activated protein kinase (ERK-1/2) phosphorylation in response to PDGF or EGF did not differ among Stat1^–/– and wild-type fibroblasts. However, Stat3 phosphorylation induced by PDGF, EGF, or IFN- increased twofold in Stat1^–/– fibroblasts compared to wild-type fibroblasts. Our findings indicate that Stat1^–/– mice are more susceptible to bleomycin-induced lung fibrosis than wild-type mice due to 1) enhanced fibroblast proliferation in response to growth factors (EGF and PDGF), 2) stimulation of fibroblast growth by a Stat1-independent IFN- signaling pathway, and 3) increased activation of Stat3.

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