Immunohistochemical changes in matrix metalloproteinase-2 and 9 during small bowel allograft rejection in rats

Kimizuka, Kei; Fujisaki, Shigeru; Park, Y.; Inoue, Masatoshi; Sugitou, Kiminobu; Tomita, Ryouichi; Fukuzawa, Masahiro; Matsumoto, Koshi

doi:10.1016/s0041-1345(02)02706-9

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…Treating the cadaveric donor with systemic MMP inhibition could, at the same time, protect other organs through organselective MMP inhibition. MMPs increase after injury in other organs, such as small intestine, (34,35) lung, (36,37) pancreas, (38) heart, (39,40) and kidney, (41,42) as well as various other organs. VEGF and sdf1 signaling recruits endothelial progenitor cells to the lung, (43) heart, (44,45) kidney, (46) and various other organs.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Rat Steatotic Liver to Ischemia–Reperfusion Is Treatable With Liver‐Selective Matrix Metalloproteinase Inhibition

et al. 2020

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Background and Aims This study examined whether enhanced susceptibility of steatotic liver to ischemia–reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury. Approach and Results Hepatic vessels were clamped for 1 hour in rats fed a high‐fat, high‐fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP‐9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver‐selective MMP‐9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15 weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)–stromal cell–derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver‐selective MMP‐9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP‐9 ASO or intraportal MMP inhibitor in 5‐week and 10‐week HFHF rats enhanced hepatic VEGF–sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5 weeks and by 80% and 64% at 10 weeks of the HFHF diet, respectively. After I/R injury in 15‐week HFHF rats, the MMP inhibitor reduced active MMP‐9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5‐week HFHF rat reduced ALT by 71% and reduced necrosis. Conclusions Lack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver‐selective MMP‐9 inhibition enhances VEGF–sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.

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