Efeito da administração do antagonista de receptor CXCR2 no modelo de fibrose pulmonar induzida por bleomicina

Abstract

Pulmonary fibrosis is a disease characterized by progressive interstitial collagen deposition, which causes changes in the normal lung architecture and loss of function, which could lead to death. Acute pulmonary inflammatory processes and their chronification are associated with fibrotic phenomena acting as triggering events. The inflammation that precedes the emergence of pulmonary fibrosis is characterized by an increased cell influx, which culminates in the liberation of inflammatory mediators, which perpetuate the initial lesion. Therefore it is likely that the inhibition of the inflammatory response might be able to decrease the interstitial collagen deposition. The bleomycin-induced pulmonary fibrosis model is characterized by intense neutrophil influx concomitant with cytokine production, high levels of chemokines CXCL1-3/KC and CXCL1-2/MIP-2, followed by collagen deposition on the pulmonary parenchyma. In this study, we analyzed the effects of DF2162 administration, which is a CXCR2 chemokine receptor antagonist on bleomycin-induced pulmonary fibrosis model in mice. Our results show that the administration of 6 mg/kg of DF2162 twice a day significantly inhibited the neutrophilic influx peaks caused by intra-tracheal instillation of 0,125 U of bleomycin. However, DF2162 did not promote changes in the levels of modulatory cytokines such as IFN, IL-10 e VEGF, which are important for the inflammatory process. We did not observe changes in the levels of chemokines CXCL1-3/KC, CXCL1-2/MIP-2, CCL2/JE, CCL3/MIP-1 and CXCL10/IP-10 with the exception of CCL5/RANTES, whose production was inhibited and CXCL9/MIG, whose levels incresased during the early phase of DF2162 treatment. Furthermore, we observed pathological changes revealing less severe and reduced interstitial collagen deposition in the lungs of DF2162-treated animals. In spite of the observed improvement in all inflammatory aspects studied, the animals receiving DF2162 had a higher mortality (66.6%) than the animals in the control group, which showed only 25% lethality.These data suggest that the CXCR2 receptor exerts an important role in the regulation of the inflammatory process and pulmonary fibrosis induced by bleomycin. Notwithstanding, the increment in letality in the group of mice that received DF2162 treatment after bleomycin instillation is likely not associated with the fibrotic process itself, but depends on factors which shall be later studied.