Endogenously-Produced Hyaluronan and Its Potential to Regulate the Development of Peritoneal Adhesions

Abstract

Formation of peritoneal adhesions (PA) is one of the major complications following intra-abdominal surgery. It is primarily caused by activation of the mesothelial layer and underlying tissues in the peritoneal membrane resulting in the transition of mesothelial cells (MCs) and fibroblasts to a pro-fibrotic phenotype. Pro-fibrotic transition of MCs—mesothelial-to-mesenchymal transition (MMT), and fibroblasts activation to myofibroblasts are interconnected to changes in cellular metabolism and culminate in the deposition of extracellular matrix (ECM) in the form of fibrotic tissue between injured sides in the abdominal cavity. However, ECM is not only a mechanical scaffold of the newly synthetized tissue but reciprocally affects fibrosis development. Hyaluronan (HA), an important component of ECM, is a non-sulfated glycosaminoglycan consisting of N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcUA) that can affect the majority of processes involved in PA formation. This review considers the role of endogenously produced HA in the context of different fibrosis-related pathologies and its overlap in the development of PA.

Endogenously produced hyaluronan contributes to the regulation of peritoneal adhesion development

“…This effect was confirmed, for example, in dermal, cardiac, lung, renal, and liver fibrosis. 21,[29][30][31][32][33] As was reviewed in our previous study, 14 with respect to the peritoneal cavity, there are just a few studies focused on the role of endogenous HA in the regulation of ECM deposition and accompanying processes, most of them concerning the disruption of peritoneal membrane homeostasis during peritoneal dialysis. 50 Raby et al reported that a higher production of HA during peritoneal dialysis contributes to inflammation and fibrosis through the action TLR2 on MCs and the phosphorylation of ERK.…”

“…There exists evidence that HA can affect the development of fibrosis in different tissues. 14 HA is a nonsulfated glycosaminoglycan synthetized from cytoplasmic UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) by three isoforms of hyaluronan synthases (HAS1-3). Functional co-operation and negative feedback mechanisms between these isoenzymes were reported in MCs by Bart 2015.…”

“…29,34 However, there are also a few studies which describe beneficial effects of endogenously produced HA in fibrosis. 35,36 As we reviewed, 14 there is a lack of studies describing mechanism of peritoneal adhesion development concerning the regulatory properties of HA produced by cells involved in the development of adhesions or peritoneal fibrosis in general. Knowledge of the HA effect is limited to the context of peritoneal disorders like peritoneal dialysis, endometriosis, or intestinal inflammation, which can result in fibrosis or even adhesions.…”

“…A higher production of HA during fibrosis‐related pathologies, including peritoneal adhesion formation, is probably not just a consequence. There exists evidence that HA can affect the development of fibrosis in different tissues 14 . HA is a nonsulfated glycosaminoglycan synthetized from cytoplasmic UDP‐glucuronic acid (UDP‐GlcUA) and UDP‐ N ‐acetyl‐ d ‐glucosamine (UDP‐GlcNAc) by three isoforms of hyaluronan synthases (HAS1‐3).…”

Editorial of Special Issue “Hyaluronic Acid in Human Medicine”

“…The article summarises its role on pulmonary innate immunity and discusses the possible adverse effect and how to deal with them. The last review article “Endogenously Produced Hyaluronan and Its Potential to Regulate the Development of Peritoneal Adhesions” [ 10 ] deals with a specific but relatively common complication of intra-abdominal surgery. The authors are describing the role of hyaluronic acid in intra-abdominal healing, explaining on which base the peritoneal adhesions are developing and gives us the key to develop effective strategies against their formation.…”