The genetic and immunologic basis of pulmonary fibrosis is poorly understood. In rodents, intratracheal bleomycin induces rapidly progressive inflammation similar to human organizing diffuse alveolar damage (DAD), with sub-acute lung injury characterized by exudative events involving cellular infiltration, increased lung permeability, and fibrin deposition. In bleomycin-susceptible mouse strains, pro-inflammatory cytokines play a key role in initiating inflammation and lung injury, and likely mediate subsequent granulation tissue formation and associated acute collagen synthesis. By addressing mechanisms that mediate exudative events that follow inflammation and lung injury, we may develop a critical understanding of factors that promote the transition from granulation tissue to chronic fibrosis that may bear relevance to the progression of human interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF). Our published data demonstrate that interferon-gamma (IFN-gamma) plays an important role in the inflammatory and fibrotic processes in the murine bleomycin model. We found that IFN-gamma protein in bronchoalveolar lavage (BAL) fluid was significantly higher 12 to 24 h following bleomycin administration in bleomycin-sensitive but not in resistant mouse strains, and that the inflammatory and fibrotic response to bleomycin in IFN-gamma knockout mice was significantly reduced compared to sensitive wild-type controls, strongly supporting a role for IFN-gamma in mediating Neomycin-induced pulmonary toxicity. Since these studies stand in contrast to well-known direct anti-fibrotic effects of IFN-gamma, we suggest that differential effects of IFN-gamma on inflammation and fibrosis in response to bleomycin may be dependent on the timing and regulation of endogenous IFN-gamma expression, or on the dosing schedule and route of administration of exogenous IFN-gamma. Furthermore, we hypothesize that IFN-gamma-mediated bleomycin pulmonary toxicity is enhanced by up-regulation of IL-12 and IL-18, inducers of IFN-gamma, and is effected, in part, through the induction of iNOS with enhanced lung injury.
The specific aims of this proposal are: (1) to determine the role of post-exposure IFN-gamma administration on the inflammatory and fibrotic response to Neomycin, (2) to determine if IFN-gamma regulatory cytokines IL-12 and IL-18 mediate bleomycin-induced pulmonary toxicity through enhanced IFN-gamma production, and (3) to determine if IFN-gamma potentiates bleomycin-induced pulmonary toxicity through direct up-regulation of iNOS expression. Understanding the mechanisms involved in IFN-gamma mediated pulmonary inflammation and fibrosis in the murine model of bleomycin pulmonary toxicity may provide insight into mechanisms involved in pulmonary fibrosis associated with human DAD, Th1 mediated interstitial lung diseases such as sarcoidosis, hypersensitivity pneumonitis, silicosis, and possibly, IPF.
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