Fig 1: Graphics show Comparison between COVID-19 (left images), H1N1 (right upper images) and CONTROL (right lower images), regarding the density of Toluidine Blue (TB) metachromatic MCs, Tryptase+ MCs per HPF (high power field) and tissue Bradykinin receptor B1 and Bradykinin receptor B2 in the percentage of immunoexpression per HPF. (A) Metachromatic MCs stained with TB are shown (red arrows) at higher density in the COVID-19 group when compared to the H1N1 and CONTROL groups. (B) The density of Tryptase+ MCs (red arrow) was also increased in the COVID-19 group when compared to the H1N1 and CONTROL groups. (C,D) As for tissue immunostaining of Bradykinin receptors, B1R and B2R was higher in the COVID-19 group (highlighted by red arrows) in comparison to the CONTROL group. However, there was no statistically related difference with the H1N1 group. Images were scanned using the Axio Scan Z1 slide scanner (Carl Zeiss, Jena, Germany): (B–D) at 40× magnification and (A) at 63× magnification. Mann–Whitney nonparametric test. Values of p < 0.05 indicated statistical significance.
Fig 2: Mast cell degranulation and the role of its mediators in the kallikrein–kinin system (KKS). (1) Chemical mediators with anionic properties secreted by activated mast cells (MCs), such as heparin and heparan sulfate, (2) together with exposure of collagen from the subendothelial layer of the adjacent vasculature, due to vasculitis caused by SARS-CoV-2 itself or cytokine storm, promote the CAS, in which the conversion of FXII into its activated form (FXIIa) is triggered. (3) KKS initiation: FXIIa converts prekallikrein into its active form, kallikrein, initiating the KKS. Kallikrein converts HMWK and LWMK into BK and lys-BK, respectively. Both hormones interact with the B2R, constitutively expressed in healthy tissues. Kininase I cleave BK and lys-BK into DABK and lys-DABK, respectively. Both new hormones interact with B1R, activated in a manner that is focally influenced by inflammatory events. Interestingly, DABK and Lys-DABK are degraded by ACE2, losing their function. (4) The binding of BK and lys-BK/B2R, and of DABK and lys-DABK/B1R, contribute to inflammatory and hyperpermeability events associated with edema, ROS secretion, pain, cytokine storm and B1R upregulation’s positive loop.
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