Estratégias farmacológicas para indução da resolução da inflamação: estudo do efeito do tratamento com Biochanina A e da inibição do eixo HGF/MET

Abstract

The inflammatory response is a physiological and protective process of the body. However, this process can become persistent and uncontrolled due to maintenance of the offending agent or excessive activation of pro inflammatory pathways. Thus, it is necessary that an active and coordinated resolving program be initiated after the onset of the inflammatory response in order to create a favorable environment for the inflammation to end properly. Inflammation resolution comprises active cellular and molecular events that operate for a protective and physiological inflammatory response, leading to the restoration of normal tissue/organ function. However, failures in the resolution of inflammation can also lead to a maintenance of the pathological inflammatory response, resulting in a series of chronic, systemic or autoimmune inflammatory diseases. In this scenario, the improvement of the pharmacological arsenal aimed at resolution has increased in recent years. Thus, in this study, we explored therapeutic approaches aimed at activating important events for the resolution of inflammation in a scenario triggered by an excessive neutrophilic response. We investigated whether treatment with the phytochemical Biochanin A (BCA) or inhibition of the hepatocyte growth factor (HGF)/Mesenchymal Epithelial Transition (MET) signaling pathway using PF 04217903, a selective MET inhibitor, would be able to to promote pro resolving effects in mouse models of arthritis. Treatment with BCA and inhibition of the HGF/MET pathway promoted resolution of the inflammation, by reducing the accumulation of neutrophils in the synovial cavity, evidenced by the apoptosis of these cells and efferocytosis by macrophages. These events were correlated with the stimulation of signaling pathways: the PKA/cAMP signaling pathway, and production of molecules involved in the resolution of inflammation, such as Annexin A1. Furthermore, both therapeutic strategies reduced myeloperoxidase (MPO) activity and levels of IL 1β and CXCL1 were also observed in periarticular tissue. It is important to emphasize that BCA and PF 04217903 reduced the histopathological score and the hypernociceptive response. Collectively, BCA and PF 04217903 represent promising pharmacological approaches for the treatment of neutrophil mediated inflammatory diseases.