Table 1.

Cellular and signalling pathways involved in adhesion formation.

Factor	Component	Role in Adhesion Formation	Reference
Surgical Trauma		Increase of fibrin Increase levels of plasminogen activator inhibitor Induction of local inflammatory response Hypoxia and reactive oxygen species (ROS) release leading to inflammation and activation of coagulation cascade Surgical hypoxia may decrease fibrinolysis	[16,23,26,27,28,30,31,32,33,34]
Extracellular Matrix Components	Fibronectin, hyaluronic acid, glycosaminoglycans, proteoglycans	Matrix for proliferation of cellular components Secreted by fibroblasts	[35,36]
Cellular Mediators			[37,38]
	Fibroblasts and Myofibroblasts	Subperitoneal fibroblast deposition required for adhesion development Transition to myofibroblast phenotype associated with long-lasting adhesions Maturation of adhesions through collagen and extracellular matrix (ECM) production	[39,40,41,42,43,44,45,46,47,48]
	Mesothelial Cells	Potential protective role Insult induces pro-fibrotic phenotype and secretion of inflammatory mediators, cells, and ECM components that contribute to immune cell recruitment and coagulation Mesothelial to mesenchymal transition (MMT) drives adhesion formation	[49,50,51,52,53]
	Macrophages	Identified in long-lasting adhesions Fundamental in adhesion formation Secrete fibrinolytic mediators and interleukins Recruit and influence mesothelial cells	[54,55,56,57,58,59]
	Neutrophils	Recruited by activated mesothelial cells Release ROS, inhibiting fibrinolysis and exerting a direct cytotoxic effect on mesothelial cells Debated in the literature to have both a pro- and anti-adhesive effect	[50,60,61,62,63,64]
	T Lymphocytes	Persist in quality and quantity in long-lasting adhesions Th1, Th2, and Treg CD4+ phenotypes implicated in adhesion formation Produce pro-inflammatory cytokines	[54,65,66,67]
	Mast Cells	High concentrations in post-surgical adhesions Release histamines, serotonin, cytokines, serine proteases, vascular endothelial growth factor (VEGF), and chymase Deficiencies in mast cells reduce adhesion formation	[68,69,70]
Signalling Factors
	Coagulation Cascade	Production of thrombin, key activator of fibrin	[23]
	Fibrin-Fibrinolysis Balance	Disruption of balance between fibrin production and fibrinolysis leads to adhesion formation Dysregulation between plasminogen-plasmin, and plasminogen activator inhibitors (PAIs) Fibrin matrix allows fibroblast adhesion and ECM maturation	[71,72]
	Matrix Metalloproteinases	Post-surgical shifts in ratios of matrix metalloproteineases (MMPs) to tissue inhibitors of MMPs (TIMPs) MMP-2/9 proposed as markers for adhesion formation Chronic suppression of MMP/TIMP ratios lead to adhesions	[73,74,75,76,77]
	Interleukins	High concentrations in adhesion sites and some direct correlations to extend of adhesion formation Pro-inflammatory effects Increased recruitment of immune cells	[38,78,79,80,81,82,83,84,85,86]
	TNF-α	Abundant in peritoneal fluid post-surgery Increases interleukin production	[87,88]
	TGF-β	Key fibrotic mediator Elevated in adhesions Stimulates myofibroblast migration and activation Chemotactic for neutrophils, T-cells, monocytes, and fibroblasts Induces ECM production Inhibits matrix degradation by altering ratio of protease to protease inhibitors	[82,89,90,91,92,93,94]
	VEGF	Promotes angiogenesis, involved in coagulation and fibrinolysis Increases vascular permeability and promotes fibrin matrix deposition	[95,96,97]