The peritoneum plays an essential role in preventing abdominal frictions and adhesions and can be utilized as a dialysis membrane. Its physiological ultrastructure, however, has not yet been studied systematically. 106 standardized peritoneal and 69 omental specimens were obtained from 107 patients (0.1-60 years) undergoing surgery for disease not affecting the peritoneum for automated quantitative histomorphometry and immunohistochemistry. The mesothelial cell layer morphology and protein expression pattern is similar across all age groups. Infants below one year have a thinner submesothelium; inflammation, profibrotic activity and mesothelial cell translocation is largely absent in all age groups. Peritoneal blood capillaries, lymphatics and nerve fibers locate in three distinct submesothelial layers. Blood vessel density and endothelial surface area follow a U-shaped curve with highest values in infants below one year and lowest values in children aged 7-12 years. Lymphatic vessel density is much lower, and again highest in infants. Omental blood capillary density correlates with parietal peritoneal findings, whereas only few lymphatic vessels are present. The healthy peritoneum exhibits major thus far unknown particularities, pertaining to functionally relevant structures, and subject to substantial changes with age. The reference ranges established here provide a framework for future histomorphometric analyses and peritoneal transport modeling approaches.

Background: Despite its complexity, the peritoneum is usually underestimated in classical medical texts simply as the surrounding tissue (serous membrane) of the gut. Novel findings on physiology and morphology of the peritoneum and mesothelial cell exist but they are usually focused or limited to Continuous Ambulatory Peritoneal Dialysis research and practice. This review aims to expose, describe and analyze the most recent evidence on the peritoneum's morphology, embryology and physiology. Materials and Methods: A literature review was performed on Pubmed and MEDLINE. With no limit of publication date, original papers and literature reviews about the peritoneum, the peritoneal cavity, peritoneal fluid, and mesothelial cells were included (n = 72). Results: Peritoneum develops in close relationship to the gut from an early period in embryogenesis. Analyzing together the development of the primitive gut and the surrounding mesothelium helps understanding that the peritoneal cavity, the mesenteries and other structures can be considered parts of the peritoneum. However, some authors consider that structures like the mesenteries are different to the peritoneum. The mesothelial cell has a complex ultrastructural organization with intercellular junctions and apical microvilli. This complexity is further proven by the large array of functions like selective fluid and cell transport; physiological protective barrier; immune induction, modulation, and inhibition; tissue repair and scarring; preventing adhesion and tumoral dissemination; cellular migration; and the epithelial-mesenchymal transition capacity. Conclusion: Recent evidence on the anatomy, histology, and physiology of the peritoneum, shows that this structure is more complex than a simple serous membrane. These results call for a new conceptualization of peritoneum, and highlight the need of adequate research for identifying clinical relevance of this knowledge.

The peritoneum has the same developmental origin as blood vessels, is highly reactive and poorly thrombogenic. We hypothesize that parietal peritoneum can sustain development and regeneration of new vessels.

Macrophages have heterogeneous phenotypes and complex functions within both innate and adaptive immune responses. To date, most experimental studies have been performed on macrophages derived from bone marrow, spleen and peritoneum. However, differences among macrophages from these particular sources remain unclear. In this study, the features of murine macrophages from bone marrow, spleen and peritoneum were compared.

Peritoneal morphology and function are abnormal in uremia patients, but the contributing mechanisms are unclear. Here we attempted to characterize the protein targets that may be related to peritoneal change in patients with uremia and have not exposed to peritoneal dialysis fluid. Protein profiles of peritoneal fluids collected from patients with uremia and patients with normal renal function receiving laparoscopic cholecystectomy were displayed by two-dimensional gel electrophoresis (2-DE). Altered protein spots were excised and subjected to tryptic digestion followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Sixteen 2-DE protein spots were altered between two groups. Western blots confirmed that kininogen-1, apoptosis inhibitor 2, cat eye syndrome critical region protein 1, and apolipoprotein A-I had higher expression levels in the uremia samples. In contrast, synaptic vesicle 2-related protein, glial fibrillary acidic protein, and envelope glycoprotein (C2-V5 region) showed lower levels. The increased expression may result from a change in the permeability of the peritoneal membrane to middle-sized proteins or peritoneal inflammation with proteins sloughing off. All the identified proteins may provide a novel understanding of peritoneal changes caused by uremic toxins and may function as biomarkers or drug targets.

Despite intensive research efforts, there remains a need for novel methods to improve the ossification of scaffolds for bone tissue engineering. Based on a common phenomenon and known pathological conditions of peritoneal membrane ossification following peritoneal dialysis, we have explored the possibility of regenerating ossified tissue in the peritoneum. Interestingly, in addition to inflammatory cells, we discovered a large number of multipotent mesenchymal stem cells (MSCs) in the peritoneal lavage fluid from mice with peritoneal catheter implants. The osteogenic potential of these peritoneal progenitor cells was demonstrated by their ability to easily infiltrate decalcified bone implants, produce osteocalcin and form mineralized bone in 8 weeks. Additionally, when poly(l-lactic acid) scaffolds loaded with bone morphogenetic protein-2 (a known osteogenic differentiation agent) were implanted into the peritoneum, signs of osteogenesis were seen within 8 weeks of implantation. The results of this investigation support the concept that scaffolds containing BMP-2 can stimulate the formation of bone in the peritoneum via directed autologous stem and progenitor cell responses.

Peritonitis caused by LPS is a severe clinical challenge, which causes organ damage and death. However, the mechanism of LPS-induced peritonitis has not been fully revealed yet. Here, we investigated the transcriptome profile of the peritoneal tissue of LPS-induced peritonitis in mice. A model of LPS-induced peritonitis in mice was established (LPS 10 mg/kg, i.p.), and the influence of TAK 242 (TLR4 inhibitor) on the level of inflammatory cytokines in mouse peritoneal lavage fluid was investigated by using an ELISA test. Next, the peritoneal tissues of the three groups of mice (Control, LPS, and LPS+TAK 242) (n = 6) were isolated and subjected to RNA-seq, followed by a series of bioinformatics analyses, including differentially expressed genes (DEGs), enrichment pathway, protein-protein interaction, and transcription factor pathway. Then, qPCR verified-hub genes that may interact with TAK 242 were obtained. Subsequently, the three-dimensional structure of hub proteins was obtained by using homology modeling and molecular dynamics optimization (300 ns). Finally, the virtual docking between TAK 242 and hub proteins was analyzed. Our results showed that TAK 242 significantly inhibited the production of inflammatory cytokines in the peritoneal lavage fluid of mice with peritonitis, including IL-6, IFN-γ, IL-1β, NO, and TNF-α. Compared with the Control group, LPS treatment induced 4201 DEGs (2442 down-regulated DEGs and 1759 up-regulated DEGs). Compared with the LPS group, 30 DEGs were affected by TAK 242 (8 down-regulated DEGs and 22 up-regulated DEGs). A total of 10 TAK 242-triggered hub genes were obtained, and the possible docking modes between TAK 242 and hub proteins were acquired. Overall, our data demonstrated that a large number of DEGs were affected in LPS-triggered peritonitis mice. Moreover, the TLR4 inhibitor TAK 242 is capable of suppressing the inflammatory response of LPS-induced peritonitis. Our work provides clues for understanding the pathogenesis of LPS-induced peritonitis in mice.

The heparan sulfate proteoglycan syndecan-1 (CD138) was shown to regulate inflammatory responses by binding chemokines and cytokines and interacting with adhesion molecules, thereby modulating leukocyte trafficking to tissues. The objectives of this study were to examine the expression of syndecan-1 and its role in leukocyte recruitment and chemokine presentation in the microcirculation underlying the parietal peritoneum.

The pathophysiology of adhesion formation needs to be clarified to reduce the adhesion-related morbidity. The epithelial characteristics of the peritoneum suggest a protective role against adhesion formation, yet how the peritoneum is involved in adhesion formation is not well characterized. We microscopically observed an experimental model of adhesion formation to investigate the effects of an injured tissue on the opposite intact peritoneum. Adhesions were induced between injured and intact hepatic lobes, and the intact peritoneum opposite to the injured tissue was examined for 8 days. The opposite intact peritoneum was denuded of mesothelial cells for 6 hours, and the remnant mesothelial cells changed morphologically for 24 hours. The detachment of mesothelial cells allowed fibrin to attach to the basement membrane of the opposite peritoneum, connecting the two lobes. Moreover, macrophages and myofibroblasts accumulated between the two lobes, and angiogenesis occurred from the opposite intact lobe to the injured lobe. These observations indicate that an injured tissue deprives the opposite intact peritoneum of its epithelial structure and causes fibrous adhesions to the opposite intact tissue. This study implies a possible role of mesothelial cells for barrier function against adhesion formation, that is, keeping mesothelial cells intact might lead to its prophylaxis.

Tumor-associated macrophages (TAM) have been shown to support tumor growth and progression by various mechanisms. However, the roles of TAM in gastric cancer (GC) peritoneal metastasis remain elusive. To explore the roles of macrophages in the process of GC peritoneal metastasis, we performed the present study. Samples from the primary GC tumor beds, surgical margins, peritoneal metastatic lesions and surrounding tissue, and the Pouch of Douglas, were collected, fixed by formalin, and embedded with paraffin. Immunohistochemistry staining for macrophages markers was performed. The peritoneal lavage was obtained from a fraction of patients to analyze the ratios of epidermal growth factor (EGF)- and vascular endothelial growth factor (VEGF)-secreting macrophages in the peritoneal cavity. GC patients with peritoneal metastasis had increased levels of macrophages and alternatively activated macrophages in the peritoneum compared to those without dissemination. Patients bearing more macrophages in the peritoneum had a poorer prognosis. GC patients bearing peritoneal metastasis harbored an increased level of angiogenesis. Macrophages in the peritoneal cavity were a source of EGF and VEGF. Macrophages in the peritoneum of GC patients play a supportive role for peritoneal metastasis by producing EGF and VEGF. Macrophages in the peritoneum might be a therapeutic target in the future.

Transforming growth factor-β (TGF-β) is believed to play a major role in the aetiology of peritoneal endometriosis. We aimed to determine if the peritoneum is a source of TGF-β and if peritoneal TGF-β expression, reception or target genes are altered in women with endometriosis. Peritoneal fluid, peritoneal bushings and peritoneal biopsies were collected from women with and without endometriosis. TGF-β1, 2 and 3 protein concentrations were measured in the peritoneal fluid. TGF-β1 was measured in mesothelial cell conditioned media. Control peritoneum and peritoneum prone to endometriosis (within Pouch of Douglas) from women without disease (n = 16) and peritoneum distal and adjacent to endometriosis lesions in women with endometriosis (n = 15) and were analysed for TGF-β expression, reception and signalling by immunohistochemistry, qRT-PCR and a TGF-β signalling PCR array. TGF-β1 was increased in the peritoneal fluid of women with endometriosis compared to those without disease (P<0.05) and peritoneal mesothelial cells secrete TGF-β1 in-vitro. In women with endometriosis, peritoneum from sites adjacent to endometriosis lesions expressed higher levels of TGFB1 mRNA when compared to distal sites (P<0.05). The TGF-β-stimulated Smad 2/3 signalling pathway was active in the peritoneum and there were significant increases (P<0.05) in expression of genes associated with tumorigenesis (MAPK8, CDC6), epithelial-mesenchymal transition (NOTCH1), angiogenesis (ID1, ID3) and neurogenesis (CREB1) in the peritoneum of women with endometriosis. In conclusion, the peritoneum, and in particular, the peritoneal mesothelium, is a source of TGF-β1 and this is enhanced around endometriosis lesions. The expression of TGF-β-regulated genes is altered in the peritoneum of women with endometriosis and this may promote an environment favorable to lesion formation.

Injury to the peritoneum during surgery is followed by a healing process that frequently results in the attachment of adjacent organs by a fibrous mass, referred commonly as adhesions. Because injuries to the peritoneum during surgery are inevitable, it is imperative that we understand the mechanisms of adhesion formation to prevent its occurrence. This requires thorough understanding of the molecular sequence that results in the attachment of injured peritoneum and the development of fibrous tissue. Recent data show that fibroblasts from the injured peritoneum may play a critical role in the formation of adhesion tissues. Therefore, identifying changes in gene expression pattern in the peritoneal fibroblasts during the process may provide clues to the mechanisms by which adhesion develop.

Colorectal cancer is one of the most common forms of cancer. Spread of tumour to the peritoneal cavity may lead to seeding of cancer cells that adhere to and invade the peritoneal membrane causing peritoneal carcinomatosis. Matrix metalloproteinases (MMPs) play an essential role in cancer cell invasion and dissemination. The aim of this study was to evaluate the morphology and presence of matrix metalloproteinases in peritoneal carcinomatosis. Biopsy samples of the parietal peritoneum were taken from patients undergoing cytoreductive surgery for peritoneal carcinomatosis. The samples were fixed in formalin, dehydrated and embedded in paraffin prior to cutting into 4-µm slices. Staining with haematoxylin/eosin was used for morphology studies, and MMP-1, MMP-2 and TIMP-1 levels were evaluated using immunohistochemistry and light microscopy. The microscopically tumour-free areas of the peritoneal membrane were thin compared to the peripheral invasion zone and the areas invaded by tumour. Peritoneum invaded by tumour was richly vascularised and contained inflammatory cells. MMP-1 was expressed in tumour-free peritoneum and in the invasion zone between tumour and peritoneal tissue, but not in tumour-invaded areas. MMP-2 and TIMP-1 were mostly expressed in the proximity of blood vessels and inflammatory cells in tumour-invaded areas, but was not seen in tumour-free areas. MMPs play an important role in the process of cancer cell invasion of the peritoneum in peritoneal carcinomatosis. The peripheral zone of the tumour appears to be of importance for tumour invasion.

Caesarean section is a very common surgical procedure worldwide. Suturing the peritoneal layers at caesarean section may or may not confer benefit, hence the need to evaluate whether this step should be omitted or routinely performed.

Tuberculous peritonitis (TBP) mimics peritoneal carcinomatosis (PC). We aimed to investigate the discriminative use of PET/CT findings in the parietal peritoneum.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas.

Long-term peritoneal dialysis is accompanied by functional and histopathological alterations in the peritoneal membrane. In the long process of peritoneal dialysis, high-glucose peritoneal dialysis solution (HGPDS) will aggravate the peritoneal fibrosis, leading to decreased effectiveness of peritoneal dialysis and ultrafiltration failure. In this study, we found that the coincidence of elevated TGF-β1 expression, autophagy, apoptosis and fibrosis in peritoneal membrane from patients with peritoneal dialysis. The peritoneal membranes from patients were performed with immunocytochemistry and transmission electron microscopy. Human peritoneal mesothelial cells were treated with 1.5%, 2.5% and 4.25% HGPDS for 24 hrs; Human peritoneal mesothelial cells pre-treated with TGF-β1 (10 ng/ml) or transfected with siRNA Beclin1 were treated with 4.25% HGPDS or vehicle for 24 hrs. We further detected the production of TGF-β1, activation of TGF-β1/Smad2/3 signalling, induction of autophagy, EMT, fibrosis and apoptosis. We also explored whether autophagy inhibition by siRNA targeting Beclin 1 reduces EMT, fibrosis and apoptosis in human peritoneal mesothelial cells. HGPDS increased TGF-β1 production, activated TGF-β1/Smad2/3 signalling and induced autophagy, fibrosis and apoptosis hallmarks in human peritoneal mesothelial cells; HGPDS-induced Beclin 1-dependent autophagy in human peritoneal mesothelial cells; Autophagy inhibition by siRNA Beclin 1 reduced EMT, fibrosis and apoptosis in human peritoneal mesothelial cells. Taken all together, these studies are expected to open a new avenue in the understanding of peritoneal fibrosis, which may guide us to explore the compounds targeting autophagy and achieve the therapeutic improvement of PD.

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5-2124.9 vs. 161.7-1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5-392.7 vs. 116.9-240.1 μm; 291.2-551.2 vs. 250.5-362.4 μm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Mast cells (MCs) are a versatile cell type playing key roles in tissue morphogenesis and host defence against bacteria and parasites. Furthermore, they can enhance immunological danger signals and are implicated in inflammatory disorders like fibrosis. This granulated cell type originates from the myeloid lineage and has similarities to basophilic granulocytes, both containing large quantities of histamine and heparin. Immature murine mast cells mature in their destination tissue and adopt either the connective tissue (CTMC) or mucosal (MMC) type. Some effector functions are executed by activation/degranulation of MCs which lead to secretion of a typical set of MC proteases (MCPT) and of the preformed or newly synthesized mediators from its granules into the local microenvironment. Due to the potential accumulation of mutations in key signalling pathway components of corresponding MC cell-lines, primary cultured MCs are an attractive mean to study general features of MC biology and aspects of MC functions relevant to human disease. Here, we describe a simple protocol for the simultaneous isolation of mature CTMC-like murine MCs from the peritoneum (PMCs) and immature MC precursors from the bone marrow (BM). The latter are differentiated in vitro to yield BM-derived MCs (BMMC). These cells display the typical morphological and phenotypic features of MCs, express the typical MC surface markers, and can be propagated and kept in culture for several weeks. The provided protocol allows simple amplification of large quantities of homogenous, non-transformed MCs from the peritoneum and bone marrow-derived mast cells for cell- and tissue-based biomedical research.

Gastric cancer is anatomically proximal to peritoneum. Gastric cancer peritoneal metastasis is a complex biological process which is corresponded with disharmony within dysfunctional adipose tissue and metabolism reprogramming. Laminin gamma 1 (LAMC1) is highly expressed in cancer cells of peritoneal metastatic sites, however, the mechanism of LAMC1-metiated gastric cancer metastases to adipose tissue-rich peritoneum remains unclear. In our study, immunohistochemical staining, single cell sequencing, a co-culture model, luciferase reporter, RNA immunoprecipitation (RIP), Chromatin immunoprecipitation (CHIP) and single-molecular magnetic tweezers assays were conducted, and our results showed that LAMC1 related to Perilipin-1 content was highly expressed in peritoneal metastatic sites and mainly secreted by tumor cells. Gastric cancer cells secreted LAMC1 in an autocrine manner to detached from the primary site and promoted preadipocytes mature, rupture and release of free fatty acids (FFAs) in the peritoneal microenvironment to form pre-metastatic niche by the paracrine pathway. Reversely, differentiated preadipocyte-derived conditioned medium inhibited glycolysis and enhanced fatty acid oxidation (FAO) rate to promote cell proliferation, mesenchymal-epithelial transformation which led to tumor peritoneal colonization. In terms of biological mechanisms, one of differentiated preadipocyte-derived FFAs, palmitic acid-activated STAT3 inhibited miR-193a-3p by binding to its promoter directly; Using single-molecular magnetic tweezers, this binding manner was proved to be stable, reversable and ATP-dependent. Moreover, miR-193a-3p regulated LAMC1 in a post-translational manner. Furthermore, high LAMC1 expression in serum predicted a higher risk of peritoneal metastasis. In conclusion, our results illustrated that palmitic acid/p-STAT3/miR-193a-3p/LAMC1 pathway promotes preadipocyte differentiation, pre-metastatic niche formation and gastric cancer cell colonization to peritoneum.