REVIEW

International Journal of Surgery 9 (2011) 589e594

Contents lists available at SciVerse ScienceDirect

International Journal of Surgery

journal homepage: www.theijs.com

Review

Intra-abdominal adhesions: Cellular mechanisms and strategies for prevention

Allison H. Maciver, Michael McCall, A.M. James Shapiro*
Department of Surgery, University of Alberta Hospitals, 2000 College Plaza, 8215 112th Street, Edmonton, Alberta, Canada T6G 2C8

a r t i c l e i n f o a b s t r a c t

Article history: Postoperative intra-abdominal adhesions represent a serious clinical problem. In this review, we have
Received 14 April 2011 focused on recent progress in the cellular and humoral mechanisms underpinning adhesion formation,
Accepted 24 August 2011 and have reviewed strategies that interfere with these pathways as a means to prevent their occurrence.
Available online 23 September 2011
Current and previous English-language literature on the pathogenesis of adhesion formation was
identified. As the burden of surgical disease in the world population increases, and the frequency of
Keywords:
reoperation increases, prevention of adhesion formation has become a pressing goal in surgical research.
Adhesions
Ó 2011 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Cytokines
Inflammatory mediators
Cellular and humoral pathogenesis

1. Introduction obstruction and 60e70% of small bowel obstructions.3 Adhesions

can prevent a safe surgical entry into the abdomen, and also
Enduring as a surgical footprint, post-operative peritoneal increase the risk of hemorrhage and intestinal perforation. They
adhesions present a challenging problem for surgeons and their can preclude adequate surgical exposure, requiring dissection
patients. They develop following abdominal and pelvic surgery as that prolongs operative time,4 or in the case of laparoscopy,
a response to tissue trauma to peritoneal surfaces. They are nearly hampering peritoneal insufflation. They are also a significant
always encountered on reoperation: in a prospective analysis of 210 cause of female infertility and dyspareunia5 in addition to
patients undergoing a laparotomy with one or more previous urologic dysfunction.6 Pelvic pain has also been linked to adhe-
abdominal operations, 93% had adhesions, compared with 10.4% in sions although this has been debated, and their lysis is usually
first-time laparotomy patients.1 ineffective at relieving it.7 The problem is a very costly one:
In this review, we review the work that has been done to eluci- reviewing one year in the U.S. alone, Ray et al. estimated adhe-
date the pathophysiology of adhesion development with a focus on siolysis was responsible for 303,836 hospitalizations, amounting
recent studies of the cellular and humoral mechanisms. In this to 846,415 days of inpatient care and US$1.3 billion in hospitali-
context of new discoveries, we will discuss future techniques and zation and surgeon costs.5
research direction.
2. Etiology and pathogenesis
1.1. The spectrum and cost of morbidity
2.1. The peritoneum
As the incidence of abdominal surgery increases worldwide, so
does the incidence of adhesions; as longevity increases, so too does The biology of peritoneal repair is now known to involve
the incidence of relaparotomy. Though there are few cohort studies, a concert of chemical mediators, cytokines, cell types, degradation
the Surgical and Clinical Adhesions Research (SCAR) group was products, and proteases to accomplish healing. Histologically, the
formed in the UK to address the issue. In one retrospective study of peritoneum consists of two layers: a mesothelium, one cell layer
29,970 patients in the UK, in the ten years following their abdom- thick, and a connective tissue layer.8 The mesothelial layer is fragile
inal or pelvic surgery, 34.6% were readmitted a mean of 2.1 times and regenerates from injury by a simultaneous and rapid differ-
for a disorder directly or possibly related to adhesions.2 entiation over the surface, rather than from centripetal migration
The most serious complication of adhesions is intestinal from epithelial cells as is seen with healing skin.9 The implication is
obstruction, accounting for more than 40% of all cases of that large defects heal as rapidly as small ones. Interestingly, the
mesothelial layer is coated with a surfactant-like agent, surface-
* Corresponding author. Tel.: þ1 780 407 7330; fax: þ1 780 407 8259. active phospholipid (SAPL) which is theorized to serve as a “non-
E-mail address: [email protected] (A.M. James Shapiro). stick coating”.10

1743-9191/$ e see front matter Ó 2011 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijsu.2011.08.008
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590 A.H. Maciver et al. / International Journal of Surgery 9 (2011) 589e594

Normal peritoneal fluid also contains many of the plasma normal conditions, the majority of fibrinous connections are lysed
proteins. There are also many chemical mediators present, such as within a few days by locally released proteases of the fibrinolytic
interleukins, interferon-g, TNF-a, TGF-b, and VEGF.11 Additionally system.15 It is theorized that if they persist, fibroblasts may prolif-
there are circulating, free macrophages and other immune cells erate within the substrate matrix, and establish more permanent
present in the peritoneal fluid.12 connections.
Healing following surgical injury to peritoneum follows one of The physiologic fibrinolytic sequence is normally initiated by
two algorithms, as proposed by Duron et al.11 The first consists of plasmin. Plasmin is a fully active serine protease which is made
the proliferation and regeneration of the mesothelial cell layer from from plasminogen by the action of plasminogen activators (PAs).11
an origin that has yet to be clearly identified; likely candidates One PA in particular, tissue plasminogen activator (tPA), is
include totipotent underlying mesenchymal cells, or migration of responsible for producing 95% of the plasmin generated in the
cells from another site (periphery of injury, nearby sites, or via response to peritoneal injury.16 After surgery, tPA knockout mice
transformation of cells in peritoneal fluid).11 The second is centered are more susceptible to adhesions.17
on the alteration of fibrinolysis, producing a “peritoneal scar,” and is In a pathological state, plasminogen activator inhibitors (PAIs)
of interest in the context of adhesion formation. interfere with the action of PAs and the production of plasmin,
Fig. 1 synthesizes putative contributory factors for adhesion ultimately leading to an altered ability to degrade fibrin split
formation, and thereby potential targets for prophylaxis. products (fibrinolysis). It has been discovered that in peritoneal
inflammation and injury, there are two types of PAI produced: PAI-
1 (the main fibrinolytic inhibitor) and PAI-2.18,19 PAI-1 specifically
2.2. The role of fibrin
prevents the formation of plasmin by binding to and inhibiting the
activities of tPA and uPA (urokinase-like plasminogen activator).
Many believe a tipping point in adhesion formation is the local
These two serine proteases are the main activators of fibrinolysis,
balance between fibrin production and fibrinolysis. The inciting
and thus inhibition of PAI-1 prevents the degradation of fibrin.
event of a surgical trauma or inflammation of the peritoneum
Surgery dramatically diminishes fibrinolytic activity, by increasing
results in a denuded surface, submesothelial damage and injury to
levels of PAIs and by reducing tissue oxygenation.20 Eventually, in
blood vessels thereby invoking an inflammatory response.13 There
the absence of an effective fibrinolytic response, there exists a fibrin
is simultaneous activation of the coagulation cascade and fibrin
gel matrix which may serve as the scaffolding for development of
deposition at the site,14 which is additive with any bleeding.
a mature adhesion.
Mediators such as histamine and PGE2 cause increased perme-
ability of the blood vessels in the traumatized area, and a seros-
anguinous exudate rich in inflammatory cells pours forth.13,15 2.3. Cellular players
The exudate also contains substrates such as fibronectin, hya-
luronic acid, various glycosaminoglycans (GAGs), and proteogly- Following trauma, initial inflammatory cells are predominantly
cans (PGs).14 The inactive fibrinogen turns to a tacky fibrin matrix neutrophils, with a shift to mostly macrophages at 24 h. Interest-
gel, which may develop between two unrelated structures. Under ingly, macrophages at the peritoneal injury site after surgery have

Fig. 1. Summary of post-surgical adhesion formation. Trauma to peritoneal and other intra-abdominal tissue results in an exudate rich in proinflammatory cytokines and various
cell types. These in turn serve to activate the coagulation cascade and a fibrin mesh forms, eventually resorbing or maturing into an adhesive connection between the surfaces.
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been found to differ from resident macrophages. These post- clear. In vitro, TGF-b reduces peritoneal fibrinolytic capacity, an
surgical macrophages secrete substances such as cyclooxygenase important step in disbanding of early adhesions.40 Interestingly, it
and lipoxygenase metabolites, plasminogen activator (PA), plas- has been observed in human peritoneal tissue that TGF-
minogen activator inhibitor (PAI), collagenase, elastase, interleu- b expression covaried with PAI-1, the main fibrinolytic inhibitor.
kins 1 and 6, tumor necrosis factor (TNF), leukotriene B4, and Patients with more extensive adhesions had higher peritoneal
prostaglandin E2.13,21 They also have the ability to recruit new concentrations of TGF-b.41
mesothelial cells to the site of the injury.22
Peritoneal macrophages in particular have been implicated as 2.4.2. VEGF
key players in the immune response triggering adhesion formation. Vascular endothelial growth factor (VEGF) is known as a potent
They have a unique autocrine activation system whereby a che- angiogenic factor and may have a role in adhesion develop-
mokine (CCL1) and its receptor (CCR8) are released in response to ment.42,43 It is also directly involved in early inflammatory
tissue damage. Migration of peritoneal macrophages (and the processes and wound healing by effects on fibroblast function.44
development of adhesions) has been interrupted and adhesion In an animal model, intraperitoneal treatment with an antibody
incidence reduced by abrogating the CCL1/CCR8 interaction.23 to VEGF has resulted in a lower incidence of advanced
There is some evidence to suggest that fibroblasts play a major adhesions.45
role in adhesion maturation. Fibroblast content increases in the
second week post-trauma, followed by the inclusion of vessel 2.4.3. Interleukins
structures and connective tissue elements.24,25 At three weeks, the Other mediators, such as interleukins, are receiving attention for
development of the adhesion becomes quite prominent.26 Rout their role in adhesion development. Comparing serum and peri-
et al. isolated fibroblasts from normal peritoneum and adhesions, toneal fluid levels of interleukin-1 (IL-1), post-operative patients
and found that they differed markedly in their phenotype.27 There have a significantly higher level in the peritoneum, suggesting
were marked effects of hypoxia and TGF-b on the expression of a possible local action of this interleukin.46 Rats treated pre-
some of these products in the fibroblasts, suggesting some, but not operatively with anti-IL-1 had fewer adhesions postoperatively
exclusive, regulatory influence of these on the pathway.27 than controls.47 Based on these and other observations, a likely
Higher levels of degranulated mast cells have also been found in mode of action of IL-1 is to promote adhesion formation by
the presence of adhesions in rats,28 and the early event of release of increasing fibrin deposits, reducing fibrinolysis, and stimulating
vascular endothelial growth factor (VEGF) by mast cells has been mesothelialization of the structure.12
suggested to be important in adhesion development.29 Further Interleukin-6, interleukin-8 and interleukin-10 are all theorized
analysis of the cellular elements of adhesions by Binnebosel et al. to participate in modulation of the cellular response to peritoneal
has shown infiltrates of macrophages and T-cells, in consistent injury, however the roles are still not clear.12 Mesothelial cells are
quantities regardless of the maturity of the adhesion.30 This char- the principal IL-6 secreting cells in the peritoneal cavity, and on
acterization of a state of chronic inflammation suggests T-cells may challenge by inflammation they produce large amounts of this
play a role in signaling pathways that maintain adhesions, and cytokine.48 Interleukin-6 is known for both pro- and anti-
prompts consideration of adhesions as a dynamic process in inflammatory effects. When complexed with its receptor (IL-6/
remodeling tissue.30 Certainly it is clear that adhesions can re-form sIL-6R) found on invading neutrophils, it influences a shift from
after adhesiolysis.31e34 leukocyte recruitment in the acute phase of inflammation to an
The infiltration of T-cells and the perpetuation of chronic influx of sustained mononuclear leukocytes.49 A recent murine
inflammation in the peritoneum proceed under the influence of study found that adhesions were prevented when cold saline was
many signals, including the promoting effects of IL-6 and other infused intraperitoneally, and this correlated with lower serum IL-6
cytokines.35 T-cell depletion and adoptive transfer experiments and elevated IL-10.50 Intraperitoneal injection of exogenous IL-10
have confirmed that adhesion formation requires the presence of has been shown to reduce post-operative adhesion formation in
CD4þ alpha beta T cells, and the production of proinflammatory a mouse model.51
cytokines are dependent on T cells (IL-17 and others).36 Since many
fibrotic tissue disorders share a common etiology of T cell-mediated 2.4.4. Tumor necrosis factor-alpha
abnormalities in host defense, adhesions represent an example of Tumor necrosis factor-alpha (TNF-a) is able to promote
this. production of interleukins by mesothelial cells,52 and high levels of
TNF-a in peritoneal fluid and serum postoperatively have corre-
2.4. Humoral mediators lated with adhesion severity in rats.53 However, administration of
neutralizing anti-TNF-a antibodies failed to reduce adhesion
Immune responses, including cell trafficking, are accomplished formation, and requires further study.47
at the cellular level by the orchestrated release of cytokines and
chemokines. Whether adhesion formation represents an abnormal 2.4.5. MMPS and TIMPS
or disordered version of peritoneal healing may be considered by Matrix metalloproteinase enzymes (MMPs) and tissue inhibitors
examining the roles of various signaling molecules that appear of matrix metalloproteinases (TIMPs) vary between individuals,
along the course of events. and lower levels of TIMP-2 in peritoneal fluid and serum is
protective.54
2.4.1. TGF-beta
Transforming growth factor beta (TGF-b) is the most studied 3. Prevention
cytokine in the pathophysiology of adhesion development, and has
been suggested as the principal profibrotic mediator of the Enormous effort both in the laboratory and the operating
process.37 In an animal model, it has been shown that intraperi- theater has been applied to reduce adhesion formation. The most
toneal application of TGF-b to surgical adhesions resulted in common and modern approaches have been the use of a barrier
worsening of the adhesions compared with controls not given TGF- between or over damaged surfaces, administration of pharmaco-
b38 and animals given TGF-b-neutralizing antibody have shown logical agents, or a combination of these. Recent reviews include
reduced adhesion formation39 In humans, the relationship is less three Cochrane reviews which compare existing evidence.55e57 Our
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592 A.H. Maciver et al. / International Journal of Surgery 9 (2011) 589e594

focus is on methods with particular reference to interruption and mechanical removal by lavage and by hand has produced incon-
modification of cellular peritoneal healing. sistent and anecdotal results.
Other targets of the fibrin-fibrinolysis pathway include use of
3.1. Barriers fibrinolytic drugs and plasminogen activating factor.58,73,81e83
These have been effective in a dose-dependent manner84 but are
Preventing contact of two traumatized surfaces with a mechan- noted to impair wound healing. Ancrod, an experimental defib-
ical barrier has been a recurring theme in efforts to reduce adhe- rinogenating agent made from Malayan pit viper venom, has been
sions. Many hold the view that critical events in adhesion formation used experimentally in combination with a hydrogel to reduce
occur by day 7,58e61 so perhaps a barrier need only be present adhesions.85 Since all fibrinolytic drugs can incite bleeding,
during an early critical window. acceptance for routine use in the prevention of post-operative
The mesothelial cell layer of the peritoneum is coated with adhesions is unlikely.
a natural anti-stick coating: a thin film of surface-active phospho- There may be a role for several medications approved for other
lipid.10 Experimental application of exogenous phospholipids has indications, such as mitomycin C, paclitaxel, sirolimus and taur-
been promising; phosphatidylcholine, sphingolipid, and gal- olidine. Mitomycin C is an antitumor antibiotic that can inhibit
actolipid62 have decreased the areas of post-operative adhesion in fibroblast proliferation for several weeks in vitro. It has been
animal studies. Phosphatidylcholine has been shown in several combined with a crosslinked hyaluronan hydrogel for the purposes
studies to have a beneficial effect in the rat,63e66 but with the side of adhesion reduction in an animal model.70 It has also been used
effect of impaired healing of intestinal anastomoses at higher locally in strabismus surgery to limit post-operative adhesion,
concentrations. Applying Poloxamer 407, a polymer of hydrophilic a property which is attributed to its antifibrinolytic activity,86 and
non-ionic surfactant, after adhesiotomy in an animal model has
reduced the incidence of re-formation of adhesions. It has yet to be
studied in humans.67 Table 1
Hyaluronic acid, also called hyaluronan or hyaluronate, has long Selected clinical and pre-clinical trials of barrier and pharmacological methods of
been a subject of antiadhesion research. It is a naturally occurring adhesion prophylaxis.

glycosaminoglycan and forms a highly viscous solution to coat Reference Model

serosal surfaces. In a single intraperitoneal dose at time of opera- Barrier methods
tion, Treutner et al. found the mean area of adhesions reduced by Aloe vera gel Aysan et al., 2009 Rat
84% compared to control in their animal model.62 Other animal Soybean oil Aysan et al., 2009 Rat
Octyl methoxycinnamate Aysan et al., 2009 Rat
studies have shown a reduction of adhesion formation when the
Icodextrin diZerega et al., 2002, Clinical trial,
hyaluronic acid was applied before the trauma, but not a reduction Menzies et al., 2006 Clinical trial
in reformation after the division of existing adhesions.68,69 Phosphatidylcholine Ar’Rajab et al., 1991, Rat, Rat, Rat,
The introduction of barriers into general clinical practice has Roszga et al., 1990, Rabbit
been restricted by several factors. Though a few are commercially Snoj et al., 1992, 1993,
Treutner et al., 1995
available, drawbacks include difficulties in preparation and appli-
SprayGel Ferland et al., 2001 Pig
cation, the need for absolute hemostasis, insufficient pliability, Poloxamer 407 Steinleitner et al., 1991 Rabbit
intricate product fixation techniques, and incompatibility with Interceed DeLaco et al., 1998, Rabbit, Mouse
laparoscopic surgical procedures.70 Without clear understanding of Haney and Doty, 1992
Gore-Tex Surgical Membrane Haney and Doty, 1992 Mouse
how these agents might interfere with normal intra-abdominal
Oxidized-regenerated cellulose Haney and Doty, 1992 Mouse
wound healing, their use deserves caution. Hyaluronic Numerous. Models have
acid/hyaluronan/hyaluronate, included mouse,
3.2. Pharmacological methods and Seprafilm rat, rabbit, as well
as clinical trials
With the discovery of new components of adhesion formation, Pharmacological methods
manipulating the cellular milieu to disfavor adhesiogenesis and Aspirin Golan et al., 1995 Rat
promote normal peritoneal resolution becomes an appealing Dexamethasone Buckenmaier et al., 1999, Rat, Rat, Rat,
Gazzaniga et al., 1975, Rabbit
prospect. Hockel et al., 1987,
Many different agents have been used in the effort to arrest the Kucukozkan et al., 2004
adhesion pathway or to tip the balance in the favor of fibrinolysis Methylprednisolone Gazzaniga et al., 1975 Rat
and adhesion resorption. Drugs may be administered systemically, Estrogen Bozkurt et al., 2009 Rat
Progesterone Maurer and Guinea pig
or ideally, locally with minimal systemic effect. The peritoneal
Bonaventura, 2003
cavity is an efficient site for uptake of large molecules; even Budesonide Yeo et al., 2003 Rabbit
particles the size of cells may pass through the lymphatic lacunae Heparin Bahadir et al., 2007, Mouse, Rabbit
located in the submesothelial layer. Fukasawa et al., 1991
The inflammatory component of the pathogenesis of adhesion Tissue plasminogen activator Buckenmaier et al., Rat
1999 and others
formation has been targeted, and a variety of steroidal and anti- Streptokinase Buckenmaier et al., 1999 Rat
inflammatory drugs have been studied, including aspirin, dexa- Urokinase Buckenmaier et al., 1999 Rat
methasone, methylprednisolone, estrogen, progesterone and Ancrod Chowdhury and Rat
budesonide.71e78 However, the effectiveness of these agents has Hubbell, 1996
Mitomycin C Cubukcu et al., 2001 and Rat, Rat
not been consistent in animal models and clinical trials.79
2002, Liu et al., 2005
Heparin has been suggested in an attempt to moderate activa- Paclitaxel Jackson et al., 2002 Rat
tion of the clotting cascade and reduce fibrin deposition contrib- Tranilast Petrilli et al., 2008 Rabbit
uting to the process of adhesion formation. There is some evidence Methylene blue dye Heydrick et al., 2007 Rat
from animal models to suggest local intraperitoneal administration Taurolidine Bahadir et al., 2007, Mouse, Rat,
Tarhan et al., 2008, Rabbit
of low-dose heparin may result in fewer adhesions.80 Removal of Treutner et al., 1995
already-formed fibrin using trypsin, pepsin, papain, as well as
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AMJS is supported through a senior clinical scholarship from 1992;24(1):27e45.
Alberta Innovates-Healthcare Solutions (AIHS), AM and MM are 23. Hoshino A, Kawamura YI, Yasuhara M, Toyama-Sorimachi N, Yamamoto K,
Matsukawa A, et al. Inhibition of CCL1-CCR8 interaction prevents aggregation
both supported through the clinical investigator program (CIP) at
of macrophages and development of peritoneal adhesions. J Immunol 2007 Apr
the University of Alberta. MM is a recipient of an AIHS fellowship. 15;178(8):5296e304.
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Allison H. Maciver MD differ between fibroblasts of adhesion and normal human peritoneum. Reprod
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study on the role of mast cells in peritoneal adhesion formation. East Afr Med J
Michael McCall MD 1999 Apr;76(4):233e6.
Contributed to the critical review of the manuscript. 29. Cahill RA, Wang JH, Soohkai S, Redmond HP. Mast cells facilitate local VEGF
A.M. James Shapiro MD PhD release as an early event in the pathogenesis of postoperative peritoneal
adhesions. Surgery 2006 Jul;140(1):108e12.
Contributed to the analysis of data and the writing and revision 30. Binnebosel M, Rosch R, Junge K, Lynen-Jansen P, Schumpelick V, Klinge U.
of the manuscript. Macrophage and T-lymphocyte infiltrates in human peritoneal adhesions
indicate a chronic inflammatory disease. World J Surg 2008 Feb;32(2):296e304.
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Acknowledgments etiology, pathophysiology, and clinical significance. Recent advances in
prevention and management. Dig Surg 2001;18(4):260e73.
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preparation of Fig. 1. angiogenesis. Dis Colon Rectum 2006 Dec;49(12):1885e92.
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