Pathophysiology of the peritoneum


Despite the clinical importance of the condition, PC has received relatively little attention in the basic science literature. The rapidly evolving knowledge about the metastatic process in human cancerogenesis can, however, be applied in part to the mechanisms giving rise to PC.

Since the original description of the "seed and soil" hypothesis by Paget, the importance of a specific host environment has been recognised as a key factor in the development of tumor metastasis. The peritoneal cytokine, adhesion molecule and growth factor environment largely determines the growth of cancerous implants on the peritoneal mesothelium. This environment undergoes important changes following both open and laparoscopic surgical interventions.(2) Surgical injury to the peritoneum triggers the mesothelial cells and peritoneal fibroblasts to an inflammatory response involving the release of a series of cytokines (IL-1, IL-6, TNF-alpha), growth factors (FGF, EGF, VEGF) and chemotactic factors.(3) Mesothelial cells were also shown to produce several adhesion molecules, P-cadherin appearing to be the dominant one. (4) Several of these factors are known to stimulate tumor growth. Indirect evidence for this mechanism is supplied by experiments aiming to avoid or interfere with the mesothelial inflammatory response. In an in vitro assay, Alkhamesi et al. demonstrated a significant decrease in peritoneal ICAM-1 expression and tumor cell adhesion by the administration of heparin. (5)
Shaheen et al. recently reported that administration of antibodies against the VEGF and EGF receptors significantly decreased tumor vascularity, tumor growth, and ascites formation in a mouse PC model. (6)

The development of PC involves a number of well defined steps: shedding and transport of loose cancer cells, adhesion to the mesothelial layer, and invasion of the peritoneum and subperitoneal tissue.

Isolated tumor cells can originate from spill during surgery or from exfoliation from the serosal surface of an established cancer. When peritoneal washings from colon cancer patients are analysed with molecular techniques (RT-PCR), micrometastatic cells can be detected in up to 24% of patients. (7)
Loose cells are transported throughout the abdomen by the physiological peritoneal fluid flow. The diaphragm and greater omentum, where absorption of particulate matter occurs, are therefore frequent locations of PC.

Adhesion of cancer cells to the mesothelial lining is mediated by a complex interaction of adhesion molecules. Although the precise mechanisms are not fully understood, several molecules have been reported to play a role in tumor-mesothelium interaction including ICAM-1, CD44, and the integrin superfamily. (8-10) Tumor adherence is rapidly followed by a destruction of the mesothelial layer characterized by tumor-induced apoptosis of mesothelial cells, mediated at least partly by a Fas-dependent mechanism.(11)
Once the peritoneal barrier has been invaded, further growth of peritoneal metastases occurs into the submesothelial connective tissue.

References

  1. Jayne DG, Fook S, Loi C, and Seow-Choen F. Peritoneal carcinomatosis from colorectal cancer/./ /British Journal of Surgery /2002; *89*: 1545-50.
  2. Bergstrom M, Ivarsson ML, and Holmdahl L. Peritoneal response to pneumoperitoneum and laparoscopic surgery/./ /British Journal of Surgery /2002; *89*: 1465-9.
  3. Jayne DG. The molecular biology of peritoneal carcinomatosis from gastrointestinal cancer/./ /Annals Academy of Medicine Singapore /2003; *32*: 219-25.
  4. Chen GTC, Tai CT, Yeh LS, Yang TC, and Tsai HD. Identification of the cadherin subtypes present in the human peritoneum and endometriotic lesions: Potential role for P-cadherin in the development of endometriosis/./ /Molecular Reproduction and Development /2002; *62*: 289-94.
  5. Alkhamesi N, Ziprin P, Pfistermuller K, Peck D, and Darzi A. Role of therapeutic intervention in peritoneal carcinomatosis via an ICAM-1 dependent mechanism/./ /British Journal of Surgery /2003; *90*: 6-.
  6. Shaheen RM, Ahmad SA, Liu W, Reinmuth N, Jung YD, Tseng WW/, et al./ Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors/./ /British Journal of Cancer /2001; *85*: 584-9.
  7. Aoki S, Takagi Y, Hayakawa M, Yamaguchi K, Futamura M, Kunieda K/, et al./ Detection of peritoneal micrometastases by reverse transcriptase-polymerase chain reaction targeting carcinoembryonic antigen and cytokeratin 20 in colon cancer patients/./ /Journal of Experimental & Clinical Cancer Research /2002; *21*: 555-62.
  8. Ziprin P, Ridgway PF, Pfistermuller KLM, Peck DH, and Darzi AW. ICAM-1 mediated tumor-mesothelial cell adhesion is modulated by IL-6 and TNF-alpha: A potential mechanism by which surgical trauma increases peritoneal metastases/./ /Cell Communication and Adhesion /2003; *10*: 141-54.
  9. Schlaeppi M, Ruegg C, TranThang C, Chapuis G, Tevaearai H, Lahm H/, et al./ Role of integrins and evidence for two distinct mechanisms mediating human colorectal carcinoma cell interaction with peritoneal mesothelial cells and extracellular matrix/./ /Cell Adhesion and Communication /1996; *4*: 439-55.
  10. Witz CA, Cho S, Montoya-Rodriguez IA, and Schenken RS. The alpha(2)beta(1) and alpha(3)beta(1) integrins do not mediate attachment of endometrial cells to peritoneal mesothelium/./ /Fertility and Sterility /2002; *78*: 796-803.
  11. Heath RM, Jayne DG, O'Leary R, Morrison EE, and Guillou PJ. Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction/./ /British Journal of Cancer /2004; *90*: 1437-42.
Barrier function of the peritoneum

The peritoneum has a surface area of 1.7 m roughly equivalent to that of the body. Most of the peritoneum behaves as a passive semipermeable membrane allowing a bidirectional flow of water and most solutes. Fluid exchange and solute flow are functionally related to the membrane area, changes in membrane permeability, and local blood flow. While the entire peritoneum acts as a semipermeable membrane for fluid and solutes, the passage of particulate matter such as bacteria is restricted to certain areas under normal conditions. Particulate matter can be absorbed through stomata between the mesothelial cells of the diaphragmatic peritoneum directly into specialized lymphatic channels called lacunae which underlie a fenestrated mesothelial basement membrane. These stomata are elastic and allow the passage of particles up to 10 µ in diameter, which include bacteria 0.5-2 µ in diameter. During expiration the stretching of the diaphragm causes a rapid flow into the lacunae, while during expiration the contraction of the diaphragm forces the fluid into the lymphatics. This mechanism affords a rapid initial clearing of bacteria from the peritoneal cavity.
A reverse process can be observed during shock and in the presence of severe inflammation of the peritoneum, i.e. abscesses. Under these conditions the normal peritoneum becomes permeable to bacteria, which then translocate from the bowel lumen into the peritoneal cavity or into abscesses. An inflammatory process of peritonitis causes a rapid shift from the intravascular space to the interstitial space and in the peritoneal cavity.
The ileus, which always accompanies peritonitis, causes additional fluid shifts by losses into the bowel lumen and lack of reabsorption of proximal secretions.

Intra-abdominal pressure

The loss of fluid into the interstitial space, the peritoneal cavity and the bowel lumen results in hypovolemia and increased intra-abdominal pressure. The normal intraperitoneal pressure is under 10 mmHg. An elevation above 10 mmHg is called abdominal compartment syndrome. The relationship between volume and pressure in the peritoneal cavity is not linear, but asmptotic. When a certain critical volume has been reached small additional increases in volume will lead to a disproportionate increase in pressure.
  • Mildly elevated intraabdominal pressure (10-20 mmHg) results in impaired visceral blood flow and a mechanical embarrassment of pulmonary function.
  • Moderately elevated intraabdominal pressure (20-40 mmHg) leads in addition to a decrease in venous return and thus to impairment of myocardial function and oliguria.
  • Finally, intraabdominal pressure above 40 mmHg will lead to anuria.


Immunologic function of peritoneum

Macrophages are present in high numbers at the peritoneal surface. They cause the effector cells to function immediately without prior proliferation, thus allowing a rapid immunologic response. Pattern of recognition receptors can be divided in secreted, endocytic and signalling receptors.
  • Secreted receptor molecules function as opsonins binding to the bacterial cell wall and facilitating the destruction of the cell by complement and its phagocytosis by neutrophils and macrophages.
  • Endocytic receptor molecules are present on the surface of phagocytotic cells and mediate phagocytosis and bacterial killing.
  • Signaling receptor molecules induce the expression of various immune-response genes triggering the inflammatory cytokine cascade.


These events lead to a local as well as a systemic inflammatory response. The initial step for the local inflammatory response is the migration of neutrophils from the vessel lumen into the peritoneal cavity. While being activated the neutrophils become fixed to the endothelial cell through binding between its integrin and the E- selectin of the endothelial cell. After diapedesis through the vessel wall the phagocyte migrates to the site of infection along a concentration gradient of chemoattractants such as complement and inflammatory cytokines where they phagocytize and kill the bacteria. During these events many endogenous mediators are activated. These endogenous mediators act on blood vessels leading to vasodilation, vasoconstriction, cellular aggregation, and functional impairment of endothelial cells. In addition, they depress myocardial function and cause myocardial dilatation.

Fibrin and adhesion formation

The normal peritoneum has fibrinolytic activity that decreases after laparotomy and is completely abolished during peritonitis. The loss of fibrinolytic activity is probably due to an upregulation of transforming growth factor beta-1 (TGF?b1), a potent mitogen, chemoattractant, and stimulant of collagen synthesis. The lack of fibrinolytic activity results in the persistence of fibrin, which entraps bacteria leading on one hand to the localization of the infection but on the other to the protection of the bacteria from host defenses. The bacteria in a fibrin clot and the numerous surrounding phagocytotic cells release exoenzymes and highly active oxygen compounds, which damage the tissue. This constitutes the basis for the development of abscesses, the internal milieu of which are characterized by
  • a low pH,
  • a low oxidation/reduction potential,
  • decreased bacterial killing by neutrophils
  • a high concentration of bacteria


Reference

T Hau, Peritoneal Defense Mechanisms Turk J Med Sci 33 (2003) 131-134