Sterile Injury Repair and Adhesion Formation at Serosal Surfaces

Abstract

Most multicellular organisms have a major body cavity containing vital organs. This cavity is lined by a mucosa-like serosal surface and filled with serous fluid which suspends many immune cells. Injuries affecting the major body cavity are potentially life-threatening. Here we summarize evidence that unique damage detection and repair mechanisms have evolved to ensure immediate and swift repair of injuries at serosal surfaces. Furthermore, thousands of patients undergo surgery within the abdominal and thoracic cavities each day. While these surgeries are potentially lifesaving, some patients will suffer complications due to inappropriate scar formation when wound healing at serosal surfaces defects. These scars called adhesions cause profound challenges for health care systems and patients. Therefore, reviewing the mechanisms of wound repair at serosal surfaces is of clinical importance. Serosal surfaces will be introduced with a short embryological and microanatomical perspective followed by a discussion of the mechanisms of damage recognition and initiation of sterile inflammation at serosal surfaces. Distinct immune cells populations are free floating within the coelomic (peritoneal) cavity and contribute towards damage recognition and initiation of wound repair. We will highlight the emerging role of resident cavity GATA6+ macrophages in repairing serosal injuries and compare serosal (mesothelial) injuries with injuries to the blood vessel walls. This allows to draw some parallels such as the critical role of the mesothelium in regulating fibrin deposition and how peritoneal macrophages can aggregate in a platelet-like fashion in response to sterile injury. Then, we discuss how serosal wound healing can go wrong, causing adhesions. The current pathogenetic understanding of and potential future therapeutic avenues against adhesions are discussed.

Keywords: mesothelium; peritoneal adhesions; peritoneum; post-surgical adhesions; sterile injury.

Figure 1

Development of the intra-embryonic coelomic cavity. (A) Schematic cross section human embryo of 3 weeks age. The mesoderm shows a somatic (dorsal) and splanchnic (ventral) aspect. (B) Cranio-caudal and latero-lateral folding in week 4. (C) After closure of the anterior abdominal wall the intra-embryonic coelomic cavity is formed. Organs (e.g. gut) are suspended by dorsal and sometimes ventral (not shown) mesenteries carrying blood vessels and nerves.

Figure 2

Microanatomy of mesothelial surfaces. (A, B) Cross sections of mouse abdominal wall stained with Hematoxylin & Eosin (A) and Masson’s trichrome staining (B). Scale bars: 50 µm. (C) Illustration of the structures shown in (A, B). (D) Top view on mesothelial surface stained with anti-podoplanin antibody.

Figure 3

Cells in a mouse coelomic cavity. (A, B) Peritoneal cavity lavage of healthy C57Bl/6 mice. Dimensionality reduction dimension 1 (umap1) and 2 (umap2) of myeloid lineage markers (mass cytometry) are plotted on x- and y-axis, respectively. Dots (cells) are colored by cluster (A) or marker (B). Data with kindly permission from M. Dosch and G. Beldi.

Figure 4

Post-surgical adhesion formation. (A) Overview of the peritoneal cavity before surgery. (B) Non-focal mesothelial injury such as major abdominal surgery leads to the uncontrolled aggregation of peritoneal macrophages serving as the nidus for the (C) subsequent Fibrin clot deposition. Inflammation and Coagulation inter-dependently promote the deposition of fibrin (see text). (D) Overview during or after adhesion formation. The abdominal organs (e.g., intestine) are now attached to the abdominal wall at anatomic (mesentery) and non-anatomic (adhesion) locations. (E) Mesothelial to mesenchymal transition gives rise to myofibroblasts that migrate into the wound and into the fibrin clot where they start to deposit extracellular matrix (ECM) such as collagen. (F) Adhesion formation is completed when the scar tissue is covered with mesothelium. The lesion may become fully perfused and pain-sensitive by ingrowth of blood vessels and nerves.

Figure 5

Factors influencing adhesion formation. Proposed concept of early local determinants that influence the binary outcome of adhesion formation and may be exploited therapeutically. tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator; PAI, Plasminogen activator inhibitor.