Research ArticleSURGICAL ADHESIONS

Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers

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Science Translational Medicine  28 Nov 2018:
Vol. 10, Issue 469, eaan6735
DOI: 10.1126/scitranslmed.aan6735

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Getting adhesions unstuck

Peritoneal adhesions are ectopic fibrotic tissues induced by surgical perturbations that result in postoperative morbidities such as small bowel obstruction. The cellular origin of adhesions remains unclear. Now, Tsai et al. show that mesothelial cells overlying organs and the abdominal wall give rise to adhesions after surgery in mice. The injured mesothelium up-regulated mesothelium-specific genes that were known to be highly expressed during fetal development. Targeting adhesions with antibodies against the mesothelial marker mesothelin eliminated adhesions that had formed after surgery. Injured mesothelium responded to hypoxia, and this was mediated by the HIF1α pathway. Blocking HIF1α with small-molecule inhibitors prevented adhesion formation in mice after surgery.

Abstract

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and are a major cause of postsurgical and infectious morbidity. The primary molecular chain of events leading to the initiation of adhesions has been elusive, chiefly due to the lack of an identifiable cell of origin. Using clonal analysis and lineage tracing, we have identified injured surface mesothelium expressing podoplanin (PDPN) and mesothelin (MSLN) as a primary instigator of peritoneal adhesions after surgery in mice. We demonstrate that an anti-MSLN antibody diminished adhesion formation in a mouse model where adhesions were induced by surgical ligation to form ischemic buttons and subsequent surgical abrasion of the peritoneum. RNA sequencing and bioinformatics analyses of mouse mesothelial cells from injured mesothelium revealed aspects of the pathological mechanism of adhesion development and yielded several potential regulators of this process. Specifically, we show that PDPN+MSLN+ mesothelium responded to hypoxia by early up-regulation of hypoxia-inducible factor 1 alpha (HIF1α) that preceded adhesion development. Inhibition of HIF1α with small molecules ameliorated the injury program in damaged mesothelium and was sufficient to diminish adhesion severity in a mouse model. Analyses of human adhesion tissue suggested that similar surface markers and signaling pathways may contribute to surgical adhesions in human patients.

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