Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation

We have recently identified a gene named GITR ( glucocorticoid-induced TNF receptor related gene). GITR is expressed in different cells and tissues such as T lymphocytes from thymus and spleen and lymph nodes, and also in the lung. GITR ligand ( GITRL) is expressed in several cells including macrophages, B cells, denditric cells, and endothelial cells. In the present study, by comparing the responses in wild-type ( WT) mice ( GITR(+/+)) and GITR-deficient mice ( GITR(-/-)), we investigated the role played by GITR-GITRL interaction in the development of chronic lung injury caused by bleomycin instillation. When compared with bleomycin-treated GITR(+/+) mice, bleomycin-treated GITR(+/+) mice exhibited a reduced degree of i) lung infiltration with polymorphonuclear neutrophils ( MPO activity); ii) edema formation; iii) histological evidence of lung injury; iv) TNF-alpha and interleukin ( IL)-1 beta production; v) nitrotyrosine formation; and vi) NF-kappa B activation. The cotreatment of GITR(+/+) mice with Fc-GITR fusion protein ( 6.25 mu g/mouse) also significantly attenuated all of the above indicators of lung damage and inflammation. Our results clearly demonstrate that GITR-GITRL interaction plays an important role in the chronic lung injury induced by bleomycin in the mice.