Cytokine orchestration in post-operative peritoneal adhesion formation

Table 1 Overview of literature to date regarding cytokine orchestration in postoperative adhesion formation. Included in the list are cytokines, chemokines, and proteases as well as trigger enzymes

CytokineRef	Mechanism investigated	In vitro/vivo	Species	Experimental model	Effect on adhesion formation
Heparin-binding growth factor[41]	Macrophage and neutrophil omental migration	In vivo	Mouse	(1) Partial hepatectomy (2) Omental adherence	Exacerbated by Midkine- omental inflammation reduced
HGF[42]	Mesothelial cell proliferation and migration	Both	Rat	Cecal abrasion	Exacerbated by local HGF gene transfer
IFN-γ , HGF[43]	Natural killer T cell activity	Both	Mouse	Cecal cauterization	Attenuated by HGF
IL-1[44]	Nonspecific inflammation	In vivo	Rat	Cecal abrasion	Exacerbated by IL-1
IL-1, TNF[45]	Proinflammatory markers	In vivo	Human	Adhesion samples	IL-1 & TNF-α associated with adhesion
IL-1, IL-6, TNF-α[46]	Cellular mediation	In vitro	Human	Peritoneal fluid sampling	Adhesions associated with IL-6 and IL-1
IL-10[47]	Natural antiiflammatory	In vivo	Mouse	Peritoneal injury	Attenuated by IL-10 but no effect with IL-10 mAb. No associated with IL-10 levels
IL-10[48]	Immunosuppression	In vivo	Mouse	Peritoneal injury	Attenuated by IL-10
IL-1b, TNF-α, TGF-β1, IL-10, IFNg, GM-CSF[49]	Inflammatory	In vitro	Human	Peritoneal fluid sampling	Only IFN-γ and TGF-β1 associated with adhesion formation. No association found with other cytokines.
IL-6[50]	Early proinflammatory effects	In vivo	Rat	Cecal abrasion with C2H5OH	Exacerbated by IL-6, attenuated by monoclonal Ab to IL-6
PAF[51]	Early inflammatory mediators	In vivo	Rat	Uterine horn abrasion	Adhesions and IL-6 levels attenuated by Lexipafant (PAF antagonist)
Substance P[52]	Substance P mediation	In vivo	Rat	Peritoneal ischaemic buttons	Substance P and TGF-β1 as well as ICAM-1 and VCAM-1 increased
TGF[53]	TGF isoforms	In vivo	Mouse	Serosal abrasion and apposition	Exacerbated by TGF-β3, attenuated by combined TGF-β1 and TGF-β2 mAB
TGF-β[54]	TGF-β regulation of extracellular matrix	In vivo	Human	Human fibroblast culture	Dichloroacetic acid inhibited fibronectin and collagen type III expression
TGF-β[55]	Chemoattraction	In vitro	Rat	Cecal abrasion	TGF-β mRNA increased by trauma
TGF-β[56]	Mast cells	In vivo	Hamster	Uterine horn abrasion	Exacerbated by chymase inhibitor
TGF-β[57]	Chemoattraction	In vivo	Rat	Uterine horn abrasion	Exacerbated by TGF-β
TGF-β[58]	Mast cells	In vitro	Human	Cell culture	TGF-β and tryptase increased collagen
TGF-β[59]	Peritoneal repair	In vivo	Rat	Uterine horn abrasion	No antiadhesion effect of anti-TGF mAb
TGF-β[60]	Immunosuppression	In vivo	Rat	Small bowel transplant	Adhesions attenuated by tacrolimus
TGF-β[61]	Mast cells	In vivo	Rat	Uterus scraping	TGF-β increased by trauma, adhesions attenuated by chymase inhibition
TGF-β[62]	Cellular effects of Tisseel	In vitro	Human	Cell culture	Fibroblasts TGF-β reduced
TGF-β, MMP-9, TIMP-1[63]	Matrix factors	In vivo	Human	Sampled peritoneal fluid	Adhesion assoc with reduced MMP-9 but elevated MMP-9/TIMP-1 ratio
TGF-β/MDF[64]	Carboxymethylcellulose sponge	In vivo	Rat	Cecal denudation & apposition	Effect of sponge independent to cytokine release (barrier function)
TGF-β1[65]	Chemoattraction	In vitro	Human	Cell culture	TGF-β1 increased in scar tissue
TGF-β1[66]	Extracellular matrix	In vivo	Mouse	Cecal abrasion	Exacerbated by haploid insufficiency
TGF-β1[67]	Fibrinolysis	In vitro	Human	Biopsy sampling	Attenuated by TGF-β1 overexpression
TGF-β1[68]	Peritonitis	In vivo	Rat	Cecal ligation and puncture	Peritonitis upregulates TGF-β1 expression
TGF-β1[69]	Mitogenicity of macrophages & fibroblasts	In vivo	Rat	Small Bowel transection and re-anastomosis	Adhesions and TGF-1 levels attenuated by ACE inhibition
TGF-β1, MMP1&2, TPA, TIMP-1[70]	Cellular effects of seprafilm	In vitro	Human	Human fibroblast & mesothelial cell culture	No cytokine effect induced by Seprafilm (barrier effect important)
TGF-β1, TGF-β2[71]	Basal expression	In vitro	Human	Biopsy sampling	Sit-specific TGF-β1 & TGF-β3 expression
TGF-β1[72]	Cellular effects of changtong	In vivo	Rat/rabbit	Cecal abrasion	TGF-β reduced in rats
TNF, IL-1, IL-6[73]	Effects of gloves and powders	In vivo	Rat	Cecal abrasion	Adhesions increased by glove powder
TNF-α [74]	Proinflammatory effects of TNF-α	In vivo	Rat	Cecal abrasion	Adhesion formation attenuated by infliximab but no histological effect
TNF-α, IL-1[75]	Proinflammatory markers	In vivo	Rat	Cecal abrasion or small bowel resection	TNF-α appears a good biological marker for adhesion formation
TNF-α, IL-1[76]	Immunosuppression	In vivo	Rat	Cecal abrasion	Adhesion formation attenuated by mAbs to IL1 and IL-1/ TNF-α
TNF-α, IL-6[77]	Proinflammatory mediators	In vitro	Mouse	Murine macrophages	Adhesion formation attenuated by hyaluronic acid and dexamethasone
TNF-α, MMP[78]	Mesothelium reaction to peritoneal injury	In vivo	Rat	Peritoneal wounding	No effect of MMP & TACE inhibition, TNF-α may not be adhesiogenic
TNF-α, TGF-β1[79]	PROACT to injured peritoneum	In vivo	Human	Tissue sampling	TNF-α and TGF-β reduced by heating
VEGF[80]	Angiogenesis	In vivo	Rat	Uterus-peritoneal scrub	Associated by angiogenesis
VEGF[29,32]	Vascular permeability	In vivo	Mouse	Peritoneal injury	Adhesions attenuated by Antiserum and monoclonal antibody
VEGF, basic-FGF[25]	Fibrovascular band formation	In vivo	Human	Adhesion samples	VEGF in endothelial cells associated with adhesion formation
VEGF, IL-6[21]	Bacterial Translocation	Both	Mouse	Caecal abrasion & suture	Adhesions attenuated by rBPI
VEGF, PlGF[81]	Pnenumoperitoeum	In vivo	Mouse	Lap. uterine horn model	Exacerbated by VEGF and CO2
CCL 1-CCR 8[83]	Specific recruitment of peritoneal macrophages	Both	Mouse	Peritoneal ischaemic button & colitis-associated peritoneal adhesions	Unaffected by CCR8 gene deficiency and antiCCL1-neutralizing antibody
CD 28 T cell costimulatory pathway[84]	CD28 T cell costimulatory pathway/Inhibitor programmed death-1 pathway	Both	Mouse	Caecal abrasion	Exacerbated by CD28 T Cell costimulatory pathway but unaffected by death-1 pathway
Interferon-inducible protein-10[85]	Regulates influxing neutrophils, monocytes and lymphocytes	In vivo	Mouse	Peritoneal side wall injury
Broad spectrum of chemokines[86]	Broad spectrum chemokine inhibitor NR58-3.14.3	In vivo	Mouse	Peritoneal traumatization	Adhesions significantly attenuated
MCP-1[87]	Fibroblast and mononuclear cell chemotaxis	In vivo	Mouse	Peritoneal injury	Attenuated by MCP-1 antibody
MCP-1[88]	Fibroblast and mononuclear cell chemotaxis	In vivo	Human	Cell culture
MCP-1[89]	Fibroblast and mononuclear cell chemotaxis	In vivo	Human	Cell culture
T cells, IL-17, CXC MPI-2/CXCL8, CXCL1[90]	CD4+ T cells	In vivo	Mouse	Caecal abrasion	Unaffected by anti-IL-17 antibodies

HGF: Hepatocyte growth factor; IFN-γ: Interferon-gamma; IL: Interleukin; TNF-α: Tumour necrosis factor-alpha; TGF-β: Transforming growth factor-beta; GM-CSF: Granulocyte macrophage colony stimulating factor; PAF: Platelet activating factor; MMP: Matrix metalloproteinase; TIMP: Tissue inhibitor of metalloproteinase; MDF: Macrophage deactivating factor; TPA: Tissue plasminogen activator; VEGF: Vascular endothelial growth factor; FGF: Fibroblast growth factor; PIGF: Placental growth factor; MCP: Monocyte chemotactic protein.