Modulation of transgene expression in mesothelial cells by activation of an inducible promoter

Background: The efficacy of peritoneal dialysis and its success as a long-term treatment depends on the preservation of the integrity of the peritoneal membrane. With increasing time on dialysis, the membrane may become compromised resulting in decreased dialysing capacity. We have pursued an innovative strategy, i.e. genetic modification of the mesothelial cell to change the properties of the membrane to potentially improve its dialysing capacity and longevity, and have demonstrated the feasibility of this approach in a rat model of ex vivo gene transfer. The potential to regulate transgene expression in this model is examined here. Methods: Rat peritoneal mesothelial cells (MCs) were stably modified to express human growth hormone (hGH) under control of the heavy metal ion and glucocorticoid-regulatable murine metalothionein-1 promoter. The effect of zinc and the synthetic glucocorticoid dexamethasone on the hGH expression was analysed in MC clones maintained in continuous passage or stationary phase, and in our rat model of ex vivo gene transfer. Results: Exposure of these clones to zinc and dexamethasone, either singly or in combination, resulted in significant (i.e. 2-200-fold) increases in hGH production. Zinc-induced modulation of hGH production was demonstrated in cells in continuous passage and stationary culture. Regulation was also demonstrated after ex vivo gene transfer by both the intraperitoneal administration of zinc ions or the systemic administration of dexamethasone. Conclusions: Our results demonstrate the modulation of transgene expression in MCs in vitro and in vivo , and suggest the potential for the regulation of gene expression in a genetically modified mesothelium that may ultimately be used for the delivery of therapeutic proteins to maintain peritoneal membrane viability in the peritoneal dialysis patient. Key words: dexamethasone; ex vivo gene transfer; gene therapy; heavy metal ions; human growth hormone; inducible promoter; intraperitoneal; mesothelial cells; mMT-1; peritoneal cavity; peritoneal dialysis; peritoneal mesothelium; systemic delivery      

Anti-beta1 integrin antibody reduces surgery-induced adhesion of colon carcinoma cells to traumatized peritoneal surfaces

OBJECTIVE: To study the mechanisms behind surgery-induced augmentation of tumor outgrowth. SUMMARY BACKGROUND DATA: Surgery provides the best chance of cure for most primary intra-abdominal carcinomas. Effective treatment is however relatively frequent complicated by peritoneal recurrences, which often originate from free-floating intraperitoneal tumor cells that implant on peritoneal surfaces. We previously reported that surgical trauma promotes development of peritoneal metastases. METHODS: Evaluation of adhesion of CC531s rat colon carcinoma cell line intraperitoneally after laparotomy using in vivo, ex vivo, and in vitro models. Also, human ex vivo models were used to study peritoneal tumor cell adhesion. RESULTS: Peritoneal imprints of operated rats showed that direct damaging of the peritoneum resulted in enhanced adhesion of rat CC531 colon carcinoma cells to submesothelial extracellular matrix (ECM) proteins in vivo, which was confirmed by electron microscopy. Additionally, the inflammatory reaction of the peritoneal cavity led to retraction of mesothelial cells, hereby also exposing ECM at peritoneal surfaces that had not been traumatized directly. Furthermore, we demonstrated that beta1 integrin subunits represented the primary mediators involved in adherence to either isolated ECM components or excised traumatized rat and human peritoneum. Importantly, incubation of CC531s cells with anti-beta1 integrin antibodies resulted in a significant decrease of tumor cell adhesion in vivo. CONCLUSIONS: Surgical trauma results in exposure of ECM at directly and nondirectly damaged peritoneal surfaces, leading to increased beta1 integrin-dependent tumor cell adhesion. Perioperative therapies, which aim to block beta1 integrin subunits, might therefore serve as new clinical tools for the prevention of peritoneal recurrences.     

Peritoneal nebulizer: a novel technique for delivering intraperitoneal therapeutics in laparoscopic surgery to prevent locoregional recurrence

Background Peritoneal involvement is a significant issue in the treatment of gastrointestinal malignancies. Current statistics indicate that after surgical intervention, up to 20% of patients will present with locoregional metastasis. The ability to inhibit initial tumor adhesion to the mesothelial lining of the peritoneum may be considered critical in the inhibition of tumor development. This article describes, the use of a novel nebulizer system capable of delivering high-concentration, low-dose therapeutics to the peritoneal cavity. Methods For this study, 30 male WAG rats were inoculated with CC531 colorectal tumor cells. The rats were randomized into three groups: control group (n = 10), heparin-treated group (n = 10), and high-molecular-weight hyaluronan-treated group (n = 10). A peritoneal cancer index was used to determine tumor burden at 15 days. Analysis of variance (ANOVA) was used to compare multiple group means. Results Nebulization therapy was performed without any complication in the cohort. Heparin inhibited macroscopic intraperitoneal tumor growth completely (p = 0.0001) without affecting tumor cell viability. The introduction of hyaluronan attenuated both tumor size and distribution, was compared with the control group (p = 0.002). Conclusion Nebulized heparin and hyaluronic acid using a novel nebulization technique attenuates peritoneal tumor growth after laparoscopic surgery. The technique itself is easy to use and safe.     

Novel anti-adhesive barrier Biobarrier reduces growth of colon cancer cells

Background

Postoperative peritoneal carcinomatosis together with adhesion formation are considered as two major clinical complications after resection of malignant abdominal tumors, jeopardizing the beneficial effect of the curative surgery. Biobarrier is a novel anti-adhesive barrier fulfilling the criteria for a good adhesion preventive agent, possessing biochemical properties that may enable it to function as a dual efficient device, reducing both adhesion and tumor development. This study aims to evaluate the effect of novel anti-adhesive device Biobarrier on intra-abdominal tumor progression.

Materials and methods

Cells from cancer cell line BN7005H1D2 were treated with Biobarrier to determine the effect of Biobarrier on cell attachment and viability in vitro. For the in vivo experiments, bilateral peritoneal trauma was inflicted in a reproducible syngeneic rat model. To mimic the clinical situation, the animals received an intraperitoneal injection of BN7005H1D2 cancer cells at the end of surgery, resembling perioperative tumor spill after intraperitoneal instillation of Biobarrier. Animals without given anti-adhesive treatment were used as control.

Results

Biobarrier applied in vitro hindered cells from attachment to the wells. In vivo treatment with Biobarrier significantly reduced tumor growth at both sites of surgical trauma (P = 0.001 and 0.015) and other non-traumatized intraperitoneal sites (P = 0.021).

Conclusions

Biobarrier maybe effective in reducing intra-abdominal tumor cell implantation with subsequent tumor development in conjunction with peritoneal trauma in a syngeneic rat model.     

Zymosan induces nitric oxide production by peritoneal mesothelial cells

Introduction: The production of nitric oxide is an important peritoneal defense mechanism. We have evaluated the effect of various putative stimulants on nitric oxide production by peritoneal mesothelial cells. Methods: Wistar rats were randomized to either a control group or a peritonitis group (5 mg zymosan intraperitoneally). Groups of five animals were sacrificed at 4, 18, 24, 48 and 96 h after the induction of peritonitis and their peritoneal fluid was harvested for assay. Cultures of peritoneal mesothelial cells were stimulated with lipopolysaccharide, myeloperoxidase, TNFα, zymosan, peritoneal fluid from a control animal and peritoneal fluid from a peritonitis animal. Supernatants were collected after incubation for 4, 24 and 48 h for assay. The assay for nitric oxide was based upon the nitrite content of the samples. Results: The intraperitoneal administration of zymosan was associated with an increased production of nitric oxide (NO) when compared with control animals (P < 0.01). In cultures of peritoneal mesothelial cells, zymosan, but not the other putative stimulants, was associated with a marked output of nitric oxide (P < 0.001). Conclusion: Zymosan has a direct effect on peritoneal mesothelial cells, which are able to generate nitric oxide in the absence of co‐stimulatory molecules. This suggests that it may be possible to use some form of external stimulation to up‐regulate the NO response by peritoneal mesothelial cells.     

Surgical Resection of Primary Tumors in Patients Who Present With Stage IV Colorectal Cancer: An Analysis of Surveillance,Epidemiology, and End Results Data, 1988 to 2000

Background Surgical resection of the primary tumor for patients who present with incurable stage IV colorectal cancer is controversial. National practice patterns have not been described. We evaluated the use of primary tumor resection in patients presenting with stage IV colorectal cancer.Methods Patients with stage IV colorectal cancer diagnosed between 1988 and 2000 were selected from the Surveillance, Epidemiology, and End Results database. Patients undergoing primary tumor resection were analyzed on the basis of sex, race, year of diagnosis, and the anatomical site of the primary tumor. We compared the survival of resected and nonresected patients.Results A total of 17,658 (66%) of the 26,754 patients presenting with stage IV colorectal cancer underwent primary tumor resection. Patients with resected disease were more likely to be young (mean age of 67.1 vs. 70.3 years) and to have right-sided tumors (75.3%, 73.0%, and 45.6%, respectively, for right, left, and rectal; P < .001). In all age groups, patients undergoing resection had higher median and 1-year survival rates (colon: 11 vs. 2 months, 45% vs. 12%, P < .001; rectum: 16 vs. 6 months, 59% vs. 25%, P < .001) when compared with patients who did not undergo resection.Conclusions Most patients who present with stage IV colorectal cancer undergo resection of the primary tumor. The proportion of patients undergoing resection depends on patient age and race and the anatomical location of the primary tumor. The degree to which case selection explains the treatment and survival differences observed is not known. Further investigation of the role of surgery in the management of incurable stage IV colorectal cancer is warranted.Presented at the 57th Annual Cancer Symposium of the Society of Surgical Oncology, New York, New York, March 18–21, 2004.Published by Springer Science+Business Media, Inc. © 2005 The Society of Surgical Oncology, Inc.     

Comparison of Two Syngeneic Orthotopic Murine Models of Pancreatic Adenocarcinoma

ABSTRACT

Background: Pancreatic adenocarcinoma has an extremely poor prognosis. The use of appropriate in vivo models is essential in devising methods to improve treatment outcomes. Methods: A pancreatic adenocarcinoma model based on tumor injection into the pancreatic head was compared with a pancreatic tail injection model in C57/BL6 mice. The murine pancreatic adenocarcinoma cell line PAN02, dispersed in Matrigel^TM, was used for tumor induction. Results: Tumors developed in all animals in both models. Tumor size was more consistent within the pancreatic tail group at 20 days following induction, with no evidence of metastatic disease. Animals in the pancreatic head injection group showed signs of reduced health by 20 days following injection and developed jaundice. Microscopic liver metastases were noted in some of these animals at this time point. The overall survival of animals at 40 days following tumor induction was significantly lower in the pancreatic head injection group (0% vs. 35%; p < .001). Multiple liver metastases were noted in five of 10 (50%) animals in the head injection group, without evidence of peritoneal metastases. In the pancreatic tail injection group, 18 of 20 (90%) animals had multiple peritoneal metastases, and nine of 20 (45%) animals had evidence of isolated liver deposits. Tumors in both regions of the pancreas had similar histologic characteristics, with a dense fibrotic stroma at the interface between the tumor and the normal pancreas. Conclusion: Pancreatic head and tail orthotopic cancer models produce consistent tumors, but the patterns of tumor spread and survival differ according to the site of injection.     

Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation

The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells “rehabilitated” marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose‐dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co‐administration of microvesicles with anti‐CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.     

Potential role of bone marrow-derived cells in the turnover of mesothelium

Background: Bone marrow cell has been proposed as a source of new mesothelium, but supporting evidence is rare. This study examines the validity of this hypothesis by using green fluorescent protein (GFP) and Y-chromosome trackers to identify the presence of donor marrow cells in peritoneal membrane of bone marrow transplant recipient mice. Methods: Cross-gender and GFP-mismatched bone marrow transplantation was undertaken in 20 FVB mice. Five recipients were killed 2, 4, and 6 weeks and 6 months later. Peritoneal tissues were obtained for the detection of GFP and Y chromosome by immunohistochemical staining (IHC) and chromogenic in situ hybridization (CISH). Results: GFP+ cells could be found in the peritoneal membrane of bone marrow transplant recipients. However, the level of engraftment was low, accounting for 0.9%, 0.8%, 0.7%, and 2.2% of the total counted mesothelial cells in intestinal serosa at 2, 4, and 6 weeks and 6 months post-transplantation, respectively. The presence of donor marrow cells within mesothelium was again confirmed by the detection of Y-chromosome-containing cells. Moreover, Y-chromosome+ cells incorporated within the mesothelium were positively stained by anticytokeratin antibody. Conclusions: Donor marrow cells could attach to mesothelium and exhibit mesothelial marker cytokeratin in bone marrow transplant recipients. This finding suggests that bone marrow-derived cells might participate in the turnover of mesothelium.     

Morphology of the rat peritoneum after carbon dioxide and helium pneumoperitoneum: a scanning electron microscopic study

Background Laparoscopic surgery for patients with cancer has been debated because of the susceptibility that laparoscopic incisions have shown for metastatic tumor growth. Structural damage of the mesothelial layer attributable to the pneumoperitoneum may facilitate intraabdominal tumor cell adhesion and growth. The influence of carbon dioxide (CO₂) and helium pneumoperitoneum on the morphology of the peritoneum was examined.Methods A total of 50 rats received colon carcinoma (DHB/TRb) cells intraperitoneally and CO₂ (n = 25) or helium (n = 25) pneumoperitoneum at 15 mmHg for 15 min. After different periods (2, 12, 24, 48, and 96 h), the rats were killed, and the peritoneum was examined by scanning electron microscopy. Control animals (n = 5) were without pneumoperitoneum.Results The control animals and most of the rats with pneumoperitoneum showed no peritoneal alterations. In four animals of each group, inflammatory alterations of the peritoneum such as bulging and retraction of mesothelial cells were observed at different time points. Tumor cells adherent to the peritoneum were found in a total of six animals. Peritoneal carcinomatosis, tumor nodules, or infiltration of the peritoneum by tumor cells was not observed.Conclusions The study demonstrated that the morphologic integrity of the rat peritoneum is not disturbed when CO₂ or helium is used for insufflation combined with the intraperitoneal injection of carcinoma cells. Pneumoperitoneum therefore probably is not the condition causing peritoneal changes that favor intraperitoneal tumor growth.     

结直肠癌中Neu3基因的表达及产物活性的检测

目的 探讨神经苷节脂特异性的唾液酸酶（Neu3）基因与人类结直肠癌的关系。方法 用逆转录-聚合酶链反应（RT-PCR）方法检测8例结直肠癌组织和正常黏膜之间Neu3 mRNA的表达差异；用硫巴比妥酸方法（TBA）检测32例结直肠癌组织和正常黏膜中唾液酸酶活性。结果 在转录水平，8对结直肠癌组织和正常组织中，癌组织中Neu3 mRNA的表达明显高于正常组织中Neu3 mRNA的表达水平；在蛋白质翻译水平．32例结直肠癌组织中的唾液酸酶活性平均为10．60U／mg，32例正常黏膜组织中的唾液酸酶活性平均为5．51U／mg（P〈0．05）。结论 Neu3基因的编码产物-神经苷节脂特异性的唾液酸酶与结直肠癌细胞的分化和生长密切相关。Neu3基因可能与人类结直肠癌有关。     

A search for malignant cells in peritoneal fluid from patients with colorectal adenocarcinoma

Cytologic examination of peritoneal fluid aids in staging ovarian malignancies and in selecting gastric adenocarcinoma patients for intraoperative adjuvant chemotherapy. Tissue culture of peritoneal fluid could be potentially valuable in confirming cell viability and establishing sensitivity to a variety of anti-cancer agents. It also could be a more sensitive diagnostic tool than cytologic examination alone. We obtained peritoneal fluid specimens from 29 patients at the time of celiotomy: 22 had colorectal adenocarcinoma and seven were controls. Cytologic examination on a portion of each specimen produced only one positive result for malignant cells. Tissue culture of the remainder of the specimens grew cells from all but one of the patients with colon cancer; however, their morphology was similar to the fibroblasts and mesothelial cells that grew from the seven controls. We speculate that these negative results stem from the absence or reduced number of tumor cells in the specimens. Without additional refinement of our methods of specimen collection and processing, cytologic examination and tissue culture of peritoneal fluid from patients with colorectal cancer are of minimal value. Nevertheless, we believe that, with the necessary refinements, they may eventually become invaluable in the management of these patients.     

The effect of immune enhancement and suppression on the development of laparoscopic port site metastasesrid=""id=""Presented at the 6th World Congress of Endoscopic Surgery, Rome, Italy, June 1998

Background: Recent clinical case reports and experimental studies have suggested that laparoscopic cancer surgery is associated with an increased risk of tumor spread to abdominal wall wounds. While the etiology of this problem was initially believed to be related to mechanical contamination of wounds, it is now recognized that there are other contributory factors, including disturbed immune function within the peritoneal cavity. To investigate this question further, we evaluated the effect of immune modulation within an established laparoscopic cancer model. Methods: Eighteen immune-competent syngeneic rats underwent modulation of their immune system, followed 18 h later by laparoscopy with the introduction of a suspension of adenocarcinoma cells into the peritoneal cavity. Rats were randomly allocated to receive either systemic cyclosporin (immune suppresser), intraperitoneal endotoxin (immune enhancer), or no agent (controls). Seven days later, all rats were killed and their peritoneal cavity was inspected for tumor implantation and port site metastases. Results: Cyclosporin did not influence the study outcome, but tumor growth (p= 0.008) and port site metastases (p < 0.0001) were less common following the administration of intraperitoneal endotoxin. Conclusion: The results of this study suggest that the immune system plays a role in the genesis of port site metastases. A preventive role for endotoxin in patients undergoing laparoscopic cancer surgery, however, remains speculative. Received: 22 July 1998/Accepted: 23 June 1999     

Myeloperoxidase response to peritonitis in an experimental model

Introduction: Patients with peritonitis often exhibit systemic manifestations of sepsis, especially in the lungs. The aim of the present study was to evaluate the local and systemic effects of the neutrophil response to peritonitis in a rat model. Methods: Fifty Wistar rats were randomized to either a control group or a peritonitis group (5 mg zymosan intraperitoneal). Groups of five animals were killed at 4, 18, 24, 48 and 96 h for evaluation of the morphology of the peritoneum (mesothelial imprint), the number and phenotype of cells within peritoneal fluid (flow cytometry), and myeloperoxidase activity within the peritoneal fluid and distant organs (enzyme assay). Results: Zymosan produced macroscopic evidence of peritonitis and on microscopy there was disruption of peritoneal mesothelial cells. This was accompanied by an influx of neutrophils between 4 and 48 h (P < 0.001) and macrophages between 48 and 96 h (P < 0.001). There was also an increase in myeloperoxidase activity within peritoneal fluid between 4 and 48 h (P < 0.05), the lung at 4 h (P < 0.01) and the liver at 48 h (P < 0.001). Conclusion: The present study has confirmed the validity of using zymosan to create a low‐morbidity model of peritonitis. Besides the anticipated peritoneal response, there were distant effects of neutrophil activation within the lungs and liver. In the future, strategies that modulate neutrophil activation within these organs might play a useful adjunctive role in the management of patients with peritonitis.     

The inhibition of tumor cell adhesion on human mesothelial cells (HOMC) by phospholipids in vitro

Background and aims Intraperitoneal tumor cell adhesion to extracellular matrix and to mesothelial cells mediated by integrins is an important step in developing peritoneal carcinosis. In former animal studies, we could demonstrate that intraperitoneal treatment with a new phospholipid (PL) emulsion significantly reduces the amount of peritoneal carcinosis by adhesion prevention. This in vitro study tries to elucidate the influence of phospholipids on cells of the human gastric cancer cell line (NUGC-4) and the human rectal cancer cell line (HRT-18) adhering to mesothelial cells (HOMC) in a monolayer culture in vitro. Materials and methods HOMC cells were derived from omentum majus from patients undergoing elective abdominal surgery. Three passages of both cancer cell lines (NUGC-4 and HRT-18) were used. 1×10⁵/100 μl (HRT-18) or 1.2×10⁵/100 μl (NUGC-4) cells, according to forgoing dilution series, were pretreated with different concentrations of phospholipid emulsion (0.05, 0.1, 0.5, 0.75, 1% PL) stained with cell tracker chloromethyl-benzamidodialkylcarbocyanine (CM-DIL) and seeded into each well on the mesothelial monolayer. After 90 min, the number of adherent cells was counted by fluorescence microscopy at 530 and 620 nm. Additionally, flow cytometric analysis of integrin α3 and β1 expression on the tumor cell surface after treatment with phospholipids was completed. Results We found a dose dependent effect of phospholipids on both tumor cell lines causing a reduction of cell–cell adhesion. Already low concentrations of phospholipids (PL 0.5) had a significant influence. The mean cell count could be reduced from 234±12/mm² in controls to 124±41/mm² (PL 0.5; NUG-4) and from 295±49/mm² to 169±29/mm² (PL 0.5; HRT-18), respectively. Additionally, the integrin α3 and β1 expression on both cell lines could be reduced. Conclusion Our results within the scope of published data indicate that adhesion prevention is capable to reduce peritoneal carcinosis. Best of Forum Papers presented at the Annual Meeting of the German Society of Surgery, 2–5 May 2006, Berlin, Germany     

Hepatocyte growth factor prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis

BACKGROUND: Ultrafiltration failure associated with peritoneal fibrosis can lead patients to discontinue continuous ambulatory peritoneal dialysis (CAPD). It has been reported that the reciprocal imbalance between transforming growth factor-beta1 (TGF-beta1) and hepatocyte growth factor (HGF) is closely involved in the progression of tissue fibrosis. We previously showed that exogenous HGF restores the growth of human peritoneal mesothelial cells suppressed by a high concentration of D-glucose or TGF-beta1. In this study, we examined whether constitutive exposure to HGF prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis (EPS). METHODS: To establish the model, a daily intraperitoneal injection of 0.1% chlorhexidine gluconate was given to male Wister rats for 35 days. Rat peritoneal mesothelial cells (RPMCs) transfected with full-length human HGF cDNA in an expression vector (pUCSRalpha/HGF) were injected into the peritoneal cavity of the rats. Thereafter, pathological changes to the peritoneal membrane were observed, and the effect on peritoneal ultrafiltration volume was examined. RESULTS: In the model, microscopic examination revealed a progressive thickening of the submesothelial layer, and an increase in the number of capillary vessels. Peritoneal ultrafiltration volume was decreased. Interestingly, the pathological changes to the peritoneal membrane were reversed by the intraperitoneal injection of pUCSRalpha/HGF-transfected RPMCs. Furthermore, peritoneal ultrafiltration volume was increased. CONCLUSIONS: The constitutive production of HGF by UCSRalpha/HGF-transfected RPMCs can improve peritoneal fibrosis resulting in an increase in peritoneal ultrafiltration volume. This approach may have clinical application.     

The TGF-beta-induced gene product, betaig-h3: its biological implications in peritoneal dialysis.

BACKGROUND: TGF-beta is involved in peritoneal changes during long-term peritoneal dialysis (PD). TGF-beta induces betaig-h3 in several cell lines, and betaig-h3 may be a marker for biologically active TGF-beta. However, no study has reported induction of betaig-h3 in human peritoneal mesothelial cells (HPMCs) or its involvement in PD-related peritoneal membrane changes. METHODS: We used cultured HPMCs to investigate the biological roles of betaig-h3 during mesothelial cell injury and repair, employing the adhesion, spreading, scratching and cell migration assays. Changes in betaig-h3 expression after high glucose exposure in vivo were also evaluated using an animal chronic PD model. RESULTS: In vitro, TGF-beta1 induced betaig-h3 in cultured HPMCs, and betaig-h3-mediated mesothelial cell adhesion occurred via alphavbeta3 integrin. betaig-h3 enhanced mesothelial cell adhesion and migration and, in part, wound healing during mesothelial cell injury. The animal study demonstrated that compared to the control group, betaig-h3 concentrations in the dialysate effluent increased in the dialysis group with alterations in peritoneal structure and function during PD, and betaig-h3 positively correlated with peritoneal solute transport. Immunohistochemical and immunoblotting results showed that betaig-h3 localizes in the mesothelium and submesothelial matrix of the parietal peritoneum, and in the vascular endothelium of omentum. betaig-h3 protein expression was higher in the dialysis group. CONCLUSION: In vitro, betaig-h3 induced by TGF-beta1 in HPMCs improved adhesion and migration of HPMCs during wound healing. In the chronic infusion model of PD, betaig-h3 played a role in the functional deterioration of the peritoneal membrane, which is associated with fibrosis.