A comprehensive review on current understanding of bradykinin in COVID-19 and inflammatory diseases

Bradykinin, a member of the kallikrein-kinin system (KKS), is a potent, short-lived vasoactive peptide that acts as a vasodilator and an inflammatory mediator in a number of signaling mechanisms. Bradykinin induced signaling is mediated through kinin B1 (BDKRB1) and B2 (BDKRB2) transmembrane receptors coupled with different subunits of G proteins (G_αi/G_α0, G_αq and G_β1γ2). The bradykinin-mediated signaling mechanism activates excessive pro-inflammatory cytokines, including IL-6, IL-1β, IL-8 and IL-2. Upregulation of these cytokines has implications in a wide range of clinical conditions such as inflammation leading to fibrosis, cardiovascular diseases, and most recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In SARS-CoV-2 infection, bradykinin is found to be at raised levels and is reported to trigger a diverse array of symptoms. All of this brings bradykinin to the core point as a molecule of immense therapeutic value. Our understanding of its involvement in various pathways has expanded with time. Therefore, there is a need to look at the overall picture that emerges from the developments made by deciphering the bradykinin mediated signaling mechanisms involved in the pathological conditions. It will help devise strategies for developing better treatment modalities in the implicated diseases. This review summarizes the current state of knowledge on bradykinin mediated signaling in the diverse conditions described above, with a marked emphasis on the therapeutic potential of targeting the bradykinin receptor.