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

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.

Neutrophil extracellular traps orchestrate formation of peritoneal adhesions

Peritoneal adhesions are a poorly understood but highly prevalent condition that can lead to intestinal obstruction, pelvic pain, and infertility. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the process of their formation remained elusive to date. Herein, we show that neutrophil extracellular traps (NETs) serve as essential scaffold for adhesion formation and that DNases interfere with this process. Thus, peritoneal adhesions in murine models and in humans showed that these lesions are largely based on extracellular DNA derived from neutrophils. Furthermore, treatment with DNASE1 or a DNASE1L3 analog significantly reduced or even prevented peritoneal adhesions in experimental models. These data not only suggest that NET formation plays an essential role in peritoneal adhesions but also show that therapeutic application of DNases can prevent the formation of peritoneal adhesions.

Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling

Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery.

Immunocompetent cells in the tissue of adhesives of patients with adhesion process in the small pelvis

Objective: To study the morphological features and subpopulation composition of immunocompetent cells of adhesion tissue in women with adhesions of the pelvic organs.Materials and Methods: Th e study was carried out using surgical material obtained from 70 women aged 23 to 40 years. Of these, 50 tissue samples of peritoneal adhesions from patients with adhesions of organs in the small pelvis of I – II degree who underwent adhesiolysis and 20 samples of parietal peritoneum from healthy women who underwent endoscopic sterilization for contraception or completion of generative function. Th e authors used histological, immunohistochemical, and morphometric research methods.Results: Immunological changes in adhesion tissue were characterized by the activation of the T-cell link of immunity. It was confi rmed by a signifi cant increase in the content of CD4+ (p <0.001), CD8+ (p <0.001), a shift in the balance of immunoregulatory subpopulations towards CD8+, a lower indicator of the immunoregulatory index (p = 0.015), and insuffi ciency of the humoral link of immunity, namely, the absence of CD20+ content against the background of a slight increase in the CD138+ pool.Conclusion: To prevent the postoperative adhesion process in the small pelvis in patients of reproductive age, it is necessary to apply immunomodulatory therapy in the early postoperative period, which will improve the results of surgical treatment and is pathogenetically justifi ed.

Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease

Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.

Prevention of postoperative adhesions of the peritoneum

On the basis of experiments with rabbits, Lhnberg (Arch. F. Gynk., B. 115, H. 3, 1922) came to the conclusion that a harmless, easily tolerated animal substance that prevents the formation of postoperative peritoneal adhesions is liquid, ether-extracted human fat administered intraperitoneally to a rabbit in an amount of about 10 cubic meters.

Changed inflammatory markers after application of 4DryField PH for adhesion prevention in gynecological surgery

Introduction The development of peritoneal adhesions and the effects of different antiadhesion agents on such mechanisms are not fully understood. Temporary rises of the C-reactive protein (CRP) level have been reported after antiadhesion agent application. We present the changes of inflammation markers observed after use of a starch-based polysaccharide certified for adhesion prevention and hemostasis 4DF (4DryField® PH). Method Retrospective comparative analysis of inflammation markers in 40 patients undergoing laparoscopic adhesiolysis with or without adhesion prophylaxis was conducted. Statistical comparisons were performed by means of paired or unpaired t tests (for normally distributed continuous data), Wilcoxon matched pairs signed-rank tests or Mann–Whitney tests (for not-normally distributed continuous data), Mantel–Cox tests (for continuous data describing time intervals), and Fisher’s exact tests (for discrete data). Results The maximum post-operative CRP level was significantly elevated in the 4DF group (87 vs. 29%; p < 0.001), whereas leukocyte concentration and body temperature did not differ between groups. No signs of infection were detected in any of the patients and CRP levels spontaneously dropped to normal values within few days. No side effects or complications were observed in both groups. In second-look surgeries performed for other diagnoses 1–56 weeks after the first interventions, no remnants of 4DF or any peritoneal inflammatory reactions were observed. Conclusion The starch-based polysaccharide 4DF can be considered safe and does not induce inflammatory reactions of clinical significance. Further studies regarding 4DF degradation are recommended and, apart from macrophage migration, could also examine corresponding markers such as IL-6 and PCT.

P–744 The features expression of some lymphocyte markers in the pelvic peritoneal adhesions’ tissue at reproductive age women

Study question To study the expression of CD4, CD8, CD20, CD 138 in the tissue of the pelvic peritoneal adhesions at women of reproductive age. Summary answer Immunohistochemical study of pelvic adhesions revealed the CD8-positive cells is directly involved in the formation of the immune response at the late stages of adhesiogenesis. What is known already One of the reason identifies the high frequency of adhesion formation is the presence of inflammation in the abdominal cavity with different severity and origin. It is known that Insufficiency of the fibrinolytic system, increased levels of a number of cytokines, including transforming growth factor- β1, and tissue hypoxia induce neoangiogenesis and fibrotization of the fibrin matrix, which leads to the formation of adhesions. Data on expression of CD4, CD8, CD20, CD138/syndecan–1 in the pelvic peritoneal adhesions in connection with their prescription, localization and origin is absent at accessible literature. Study design, size, duration Two hundred infertile women (aged 19–49 yrs) with pelvic peritoneal adhesions, who were underwent operative laparoscopy and adhesiolysis. Participants/materials, setting, methods The material for this study was the fragments of surgical material (adhesions and their parts) n = 200, taken from the women of reproductive age who suffered with infertility during operative laparoscopy.The morphological and immunohistochemical study of adhesions were carried out by standard techniques using paraffin blocks, reagents of Dako and monoclonal antibodies to CD4 (Clone 4B12 Ready-to-Use),CD8 (Clone C8/144B Ready-to-Use), CD20 (Clone L26 Ready-to-Use),CD138/syndecan–1 (Clone MI15 Ready-to-Use) of Abcam with automatic coloring Dako Cytomation. Main results and the role of chance To assess the population composition of these cell infiltrates, as well as individual diffusely located inflammatory cells, an immunohistochemical method with the main lymphocytic markers (CD4, CD8, CD20, CD138) was used. First of all, it is necessary to note the complete absence of CD20-positively colored cells in all observations, which indicates that at the final stage of the formation of adhesions, there is no element of the B-lymphocytic immune response. In an immunohistochemical study with syndecan–1 (CD138) antibodies, we identified a small number of positively colored cells that were located mainly perivascular, as part of mononuclear infiltrates. Quantitative analysis showed that the number of such cells is 0.8±0.2. When studying CD4–positive T-lymphocytes, it was found that they are usually located in the form of band-shaped infiltrates and focal perivascular clusters. The number of CD4-positive cells in the spike tissue is 5.6±0.2. CD8-positive cells were located mainly submesothelial, and in the form of perivascular clusters, the number of such cells was 9.2±0.6. Limitations, reasons for caution Age limitation, only women aged 19–49 yrs took part in this study. Exclusion criteria were the following for the groups: acute gynecological diseases, malignant diseases of female genitalia and ovarian tumors. Wider implications of the findings: The absence of B-cells in the “mature” adhesions’ tissue was found.The number of CD8-positive cells in our study was 1.5 times higher than the number of CD4-positive T-lymphocytes.CD4-positive T-lymphocytes play an important role and their number significantly prevails over the number of CD8-positive T-lymphocytes at the initial stages of adhesiogenesis. Trial registration number Case control study