PECAM‐1 modulates liver damage induced by synergistic effects of TNF‐α and irradiation

Abstract

The mechanisms of radiation‐induced liver damage are poorly understood. We investigated if tumour necrosis factor ( TNF )‐α acts synergistically with irradiation, and how its activity is influenced by platelet endothelial cell adhesion molecule‐1 (PECAM‐1). We studied murine models of selective single‐dose (25 Gy) liver irradiation with and without TNF ‐α application (2 μg/mouse; i.p.). In serum of wild‐type (wt)‐mice, irradiation induced a mild increase in hepatic damage marker aspartate aminotransferase ( AST ) in comparison to sham‐irradiated controls. AST levels further increased in mice treated with both irradiation and TNF ‐α. Accordingly, elevated numbers of leucocytes and increased expression of the macrophage marker CD 68 were observed in the liver of these mice. In parallel to hepatic damage, a consecutive decrease in expression of hepatic PECAM ‐1 was found in mice that received radiation or TNF ‐α treatment alone. The combination of radiation and TNF ‐α induced an additional significant decline of PECAM ‐1. Furthermore, increased expression of hepatic lipocalin‐2 ( LCN ‐2), a hepatoprotective protein, was detected at mRNA and protein levels after irradiation or TNF ‐α treatment alone and the combination of both. Signal transducer and activator of transcription‐3 ( STAT ‐3) seems to be involved in the signalling cascade. To study the involvement of PECAM ‐1 in hepatic damage more deeply, the liver of both wt‐ and PECAM ‐1‐knock‐out‐mice were selectively irradiated (25 Gy). Thereby, ko‐mice showed higher liver damage as revealed by elevated AST levels, but also increased hepatoprotective LCN ‐2 expression. Our studies show that TNF ‐α has a pivotal role in radiation‐induced hepatic damage. It acts in concert with irradiation and its activity is modulated by PECAM ‐1, which mediates pro‐ and anti‐inflammatory signalling.

Leaf extracts of Campomanesia xanthocarpa positively regulates atherosclerotic-related protein expression

“…It has been previously reported that the decreased expression of ICAM-1 (Liu et al 2017) and the unstable expression of PECAM-1 can increase the permeability of the endothelium as they act as key molecules for this phenotype (Liu et al 2011, Woodfin et al 2007. This observation was corroborated by a recent study that has revealed that PECAM-1 may have anti-inflammatory and proinflammatory roles in the cells (Malik et al 2019). In addition to this process, the increase in vascular permeability is dependent on the binding of monocytes to endothelial cells, causing activation of the ICAM-1-mediated Src Kinase signaling protein (Liu et al 2012).…”

Generation of PECAM‐1 (CD31) conditional knockout mice

“…Similarly, breeding PECAM1 flox/flox mice with mice that express Cre recombinase in CD4 + T cells (Kim et al, ) can help to verify their postulated role in resistance to bacterial infection (Ross et al, ). Finally, PECAM1 flox/flox and tissue‐specific Cre recombinase‐expressing mice can be used to identify the specific PECAM‐1‐expressing cells that control inflammatory diseases of the liver (Goel et al, ; G. Malik et al, ; I. A. Malik et al, ) and lung (Schenkel et al, ), and that interfere with tumor clearance (Ma et al, ; D. K. Newman et al, ).…”

“…Thus, PECAM‐1 was found to enhance hemostasis (Lishnevsky et al, ; Mahooti et al, ) and inhibit thrombosis (Falati et al, ; Kellermair et al, ). PECAM‐1 was also found to play protective roles in autoimmunity (Cheung et al, ; Clement et al, ; Graesser et al, ), inflammatory diseases of the liver (Goel et al, ; G. Malik, Wilting, Hess, Ramadori, & Malik, ; I. A. Malik et al, ) and lung (Schenkel, Chew, Chlipala, Harbord, & Muller, ), and in sepsis (Carrithers et al, ; Maas et al, ; Privratsky, Tilkens, Newman, & Newman, ).…”

“…Thus, PECAM-1 was found to enhance hemostasis (Lishnevsky et al, 2014;Mahooti et al, 2000) and inhibit thrombosis (Falati et al, 2006;Kellermair et al, 2013). PECAM-1 was also found to play protective roles in autoimmunity (Cheung et al, 2015;Clement et al, 2014;Graesser et al, 2002), inflammatory diseases of the liver (Goel et al, 2007;G. Malik, Wilting, Hess, Ramadori, & Malik, 2019;I.…”

Development of A New Mouse Model for Intrahepatic Cholangiocellular Carcinoma: Accelerating Functions of Pecam-1

“…A single injection of TAA evokes reversible damage of the liver parenchyma in rodents [23]. We have previously shown that Pecam-1-regulated pathways play an important role during tissue damage, and we could further demonstrate liver-protective effects of PECAM-1 by using Pecam-1-deficient mice in acute inflammation models [24,25,26]. Thereby, PECAM-1 appeared to be an interesting candidate for inflammation-triggered liver cancer.…”