Intervenção farmacológica no sistema quimiocinas: possíveis alvos para o tratamento da fibrose pulmonar

Abstract

Pulmonary fibrosis is a chronic respiratory lethal disease whose clinical signs include a worsening of dyspnea, progressive loss of lung volume and abnormal gas exchange. Fibrosis may be triggered by a series of inflammatory lung condition that usually precedes the deposition of collagen in the lung parenchyma. Initially, the use of corticosteroids was used as a strategy for the treatment of pulmonary fibrosis in order to reduce the pulmonary inflammation as well fibroplasia. However, the appearance of adverse effects during the treatment period limited their therapeutic application. Clinical data have shown a close correlation between pulmonary fibrosis, levels of circulating chemokines or boncho-alveolar lavage, and white blood cell counts. In this scenario, the chemokines become important targets for the treatment of pulmonary fibrosis, since they are responsible for guiding the inflammatory and fibrogenic responses.This thesis presents a compilation study of new drugs that may inhibit lung fibrosis induced experimentally in mice and reveals different ways of intervening in the chemokine system during pulmonary inflammatory and fibrogenic process. The targets used for the study were: (i) the chemokine receptor CXCR2, (ii) the chemokine CCL3 and (iii) the common element of signaling pathway of chemokine receptors, the PI3K. The oral administration of the allosteric antagonist non-competitive of CXCR2 receptor (DF2162) in bleomycin-induced pulmonary fibrosis mice model, was responsible for the protective effect observed in animals when treated in a preventively (from day 0 to 16) or therapeutic (from day 8 to 16) schedule. The reduction of pulmonary fibrosis in those animals treated with DF2162 appeared to be caused by inhibitory effects on angiogenesis, and may even be of dual nature, via inhibition of neutrophil transmigration into the airways. Through the use of the chemokine binding proteins-CCL3 (Evasin-1), first isolated and cloned from salivary glands of Rhipicephalus sanguineus, we studied the inhibitory effects of CCL3 during bleomycin-induced pulmonary inflammation and fibrosis. Preventive (from day 0 to 25) and therapeutic (from day 8 to 25) treatments with Evasin-1 caused a reduction of pulmonary fibrosis in mice, associated with a lower leukocyte infiltration and reduced production of pro-fibrogenic cytokines. Finally, to evaluate the importance of a common element of intracellular signaling pathway used by chemokine receptors, the PI3K, in the development of pulmonary fibrosis, deficient animals for the isoform of PI3K were challenged with bleomycin. PI3K deficiency led to attenuation of fibrosis and increased animal survival, besides a reduction in leukocyte influx into the airways. The inhibition of PI3K also caused functional changes in endothelial cells and fibroblasts in vitro, suggesting that PI3K participates in the process of angiogenesis and the secretion of collagen by fibroblasts. Together, these data demonstrate a potential modulation of the chemokine system in inflammatory lung diseases context and provide new drug candidates for the pulmonary fibrosis treatment. Future clinical trials may validate their therapeutic use.