Chemokines in Radiation Induced Pulmonary Fibrosis

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a severe and often lethal complication of the thoracic radiation used to treat cancer patients. This process is initiated by oxidative damage that precedes the onset of interstitial pneumonitis and ultimately fibrosis. The molecular pathophysiology has not been extensively defined and effective preventative therapies have yet to be developed; however chemokines are potentially important mediators. Chemokines are small proteins that mediate many inflammatory responses, such as pneumonitis. We have previously shown that mice deficient in the expression of the chemokine, MIP-1alpha, are protected from the pulmonary inflammation induced by influenza virus and from graft-versus-host disease. More recently, we have also found that in comparison to wild type (wt) mice, MIP-1alpha, -/- animals are significantly protected from developing radiation-induced pulmonary fibrosis. We now propose to test the specificity of this protective effect and to test potential therapeutic agents through the following specific aims: i) To confirm a) the specific radioprotective role for MIP-Ix -/- by treating the wild-type animals with anti- MIP-1alpha monoclonal antibody at the time of irradiation and b) the role of neutrophils and CD8+ T cells in mediating fibrosis using anti-neutrophil antibodies and beta2 microglobulin-deficient mice; ii) To use receptor knockout animals to study which MIP-1alpha-binding chemokine receptor(s) are important in mediating the injury seen after irradiation; iii) To test a panel of beta chemokine inhibitors for their ability to reproduce the radioprotective effect seen in MIP- 1alpha-deficient mice. Thus, reproducing these radioprotective effects in wt animals by inhibition of MIP-1alpha binding and/or signaling would confirm its specificity and allow for kinetic determinations that would facilitate optimizing therapeutic interventions. In addition, determining which (if any) of the chemokine receptors binding MIP-1alpha are important in mediating this effect will allow future studies of potential synthetic inhibitors that may be therapeutically useful for patients receiving thoracic radiation therapy.