The role of bradykinin in lung ischemia-reperfusion injury in a rat lung transplantation model

Abstract

PURPOSE:To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS:Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO 2 ), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS:Compared to the LPD group, the AB192 group showed higher PO 2 , lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin β2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION:Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.

A brief review of interplay between vitamin D and angiotensin‐converting enzyme 2: Implications for a potential treatment for COVID‐19

“…Meanwhile, ACE2 affects biologic peptides outside the RAS such as the Kinin‐Kallikrein system, Apelin‐13 and dynorphin A peptide. These peptides can be elevated and impose unfavorable effects by attenuatingACE2 expression 38 . Furthermore, ACE2 hydrolyzes the active bradykinin metabolite DABK (desArg 9 ‐bradykinin) 39 .…”

COVID-19 interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin system; looking at a potential treatment

“…Meanwhile, ACE2 also acts on 126 biologic peptides outside the RAAS, i.e, the kinin-kallikrein system (KKS), Apelin-13 and dynorphin A peptide. These substrates could be increased and impose adverse effects with reducing the expression of ACE2 (15).…”

“…The physiologic roles of bradykinin include propagation of inflammatory processes, vascular relaxation and interaction with regional neural structures (19). Decreased levels of bradykinin may offer some protection against ischemia/reperfusion injury during lung transplantation (15). Kinins exert their pro-inflammatory actions by the selective induction of two distinct G-protein coupled receptors, bradykinin B1 receptor (BKB1R) and bradykinin B2 receptor (BKB2R).…”

Therapeutic Approaches in COVID-19 Patients: The Role of the Renin-Angiotensin System

“…Inhibition of ACE2 during inhalation of endotoxin increases BK axis activity, neutrophil infiltration, and severe inflammation in the mouse lung [67]. BK is indicated to induce lung damage in ischemia-reperfusion and inflammation caused by parainfluenza-3 [75,76]. A significant increase in BK and DABK increases vascular permeability, inflammatory reactions, and lung injury, leading to a serious illness called BK storm [77][78][79].…”