D E L I B E G OV I C PERITONITIS 133

Review Article

THE PATHOPHYSIOLOGY OF PERITONITIS

Samir Delibegovic1,2

1
Clinic for Surgery,
University Clinical Center Tuzla, ABSTRACT
Tuzla, Bosnia and Herzegovina
2
Faculty of Medicine, Peritonitis signifies inflammation of peritoneum, whose cause is
University of Tuzla, not specific. It can be regarded as local equivalent of systemic
Tuzla, Bosnia and Herzegovina
inflammatory response which is seen after any trigger of
inflammation and referred to as systemic inflammatory response
Corresponding author: syndrome (SIRS). Peritonitis takes place together with many,
Samir Delibegovic, MD, PhD, FACS
Adresss: Trnovac bb. 75 000 Tuzla, complex pathophysiological changes on systemic and cellular
Bosnia and Herzegovina level.
Phone ++38735303500
ORCID: 0000-0003-0525-3288 Keywords: Adhesion, cytokine, peritonitis, PMN
Email: [email protected]

Original Submission:
03 April 2022
Revised Submission:
21 April 2022
Accepted:
04 May 2022

How to cite this article:

Delibegović S. 2022. Pathophysiology
of peritonitis. Veterinaria, 71(2),
133-152.

doi.org/10.51607/22331360.2022.71.2.133
134 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

Physiology of the peritoneal cavity peritoneal macrophages, 44% lymphocytes, 2%

dendritic cells, and a small number of eosinophils
The peritoneum is a smooth, transparent, serous
and fat cells) (Maddaus et al., 1988). Bacteria are
membrane that coats the abdominal cavity as the
absent because peritoneal fluid has minimal anti-
parietal peritoneum, and coats the intraabdominal
bacterial activity due to the presence of comple-
organs as the visceral peritoneum. This cavity is
ment. Under normal circumstances, the presence
the largest extravascular space in the body, and
of this small amount of peritoneal fluid facilitates
the total area of the peritoneum is approximately
the mobility of the structures covered by the peri-
equal to the body surface area in adults and is
toneum. It is secreted by peritoneal serosa and
about 1.8 m2. The functional area is smaller than
absorbed, primarily, through the diaphragm. It is
the anatomical one, about 1 m2, probably due to
mainly resorbed through terminal lymphatic la-
variations in blood supply (Delibegovic, 2007).
cunae lying below the fissures (stomata, 10 to 16
There is 50-100 ml of clear, sterile serous fluid in μm in size, first described by von Recklinghausen
the peritoneal cavity. It is a plasma ultrafiltrate in 1863) in the mesothelium, below the surfaces
with electrolytes and a concentration similar to the of the diaphragm, and is further drained into the
adjacent interstitial space, and contains less than larger mediastinal lymph vessels (Nakatani et al.,
30 g/l proteins, mainly albumin. Peritoneal fluid 1996). Diaphragmatic lymph vessels allow the par-
contains a small number of desquamated mesothe- ticles to leave the peritoneal cavity. The opposite
lial cells and a variable number of morphological- flow is prevented by unilateral valves within these
ly different migrating immune cells (<300 cells/ lymphatic vessels (Heemken et al., 1997; Hall et
μl more than half of the normal cells are resident al., 1998) (Figure 1).

Figure 1 Longitudinal section of diaphragmatic lymph vessels.

 D E L I B E G OV I C PERITONITIS 135

Diaphragm movement, negative intrathoracic Numerous factors can affect this diaphragmatic
pressure, and positive intra-abdominal pressure clearance. In animal models, blocking of this
move the peritoneal fluid and particles upward mechanism was achieved by the application of talc
(Figure 2). Transport is fast and efficient. Thus, in platelets. It has been observed that reducing breath
humans, 1.0 to 3.0/l of fluid is transported daily intake, using general anesthesia, reduces this
through the left thoracic duct, which is a capaci- clearance. Even the application of PEEP (positive
ty of about 0.5 to 1.0 mg/kg/h. The total transport pressure at the end of expiration) reduces peritoneal
is probably even higher as a significant amount of bacterial clearance. Also, application of positive
fluid is also transported through the right ductus intrathoracic pressure worsens lymph flow.
lymphaticus. This clearance mechanism is im- Another clearance mechanism is phagocytosis by
portant for understanding the pathophysiology of peritoneal macrophages (Dunn et al., 1985). These
peritonitis. It explains the early systemic manifes- two effective mechanisms probably represent the
tations of peritonitis. Soon after intestinal perfo- “first line” of clearance after bacterial contamina-
ration, bacteria and their products are transported tion. Peritoneal cavity sterility can be maintained
into the systemic circulation. Intraperitoneally ad- despite many episodes of low bacterial inocula-
ministered drugs reach the systemic circulation in tion, thanks to the efficacy of these local clearance
the same way. In contrast, intravenously adminis- mechanisms. However, if these mechanisms do
tered antibiotics are rapidly found in the peritoneal not perform their function, an inflammatory re-
cavity (Al Shoyaib et al., 2019). sponse with further bacterial clearance follows, in
order to localize or stop the infection. As a bio-
logical membrane, the peritoneum transports wa-

Figure 2 Peritoneal fluid flow.

136 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

ter, electrolytes, small molecules, and some mac- Bacteriology of intra-abdominal infection
romolecules. Of the total area of the peritoneum,
The infectious flora that leads to peritonitis
the functionally absorbable area is about 50%. usually consists of polymicrobial, polyaerobic and
Electrolytes, proteins and other endogenous and polyanaerobic flora. Cultures of intraperitoneal
exogenous substances are freely absorbed. Factors infection demonstrate up to five microorganisms
thought to affect absorption include intraabdomi- per patient, although most clinical laboratories
nal pressure, fever, dehydration, shock, increased detect two to three per patient. Gram peritoneal
portal pressure, lymphatic blockage, and a thick, exudate tests usually reveal pleomorphic Gram-
scarred peritoneum. Isotonic saline, administered positive and Gram-negative bacteria.
intraperitoneally after initial equilibrium, is ab- The gastrointestinal tract is a huge reservoir
sorbed at a rate of approximately 30.0-35.0 ml per of bacteria, so much so that their amount is
hour. However, if a hypertonic saline solution is estimated at 1012 to 1014 in 1 ml of intestinal
used, there is a large displacement of water (up contents (Sender et al., 2016). They are not evenly
to 300-500 ml per hour) from the intravascular distributed in the gastrointestinal tract. In the
space into the peritoneal cavity, which can result upper parts of the tract there is only 4% of the
in hypotension and shock (Samson and Pasternak, total number of bacteria, and in the colon as much
1979). This movement of water can be enhanced as 96%. The oral cavity, esophagus and stomach
by agents that increase the blood flow or vascular are populated predominantly by Streptococci and
permeability. Peritonitis has similar effects, and Diplococci in an amount less than 1.000 bacteria
can cause rapid displacement from the intravascu- per 1 ml. The acidic environment of the stomach
lar and interstitial space into the peritoneal cavity, is not conducive to the development of bacteria.
which can cause severe hypotension. However, in patients with achloridia, gastric
cancer, and patients who are on mechanical
The movement of fluid through the peritoneum respiratory ventilation and, at the same time,
is two-way, between the peritoneal cavity and high doses of H2 blockers, the amount of bacteria
the plasma. For electrolytes, such as sodium and is higher and amounts to 100.000 to 1.000.000
potassium, transport across the membrane takes in 1 ml. The dudodenum and jejunum contain a
place by diffusion. Transcapillary transport of bacterial flora consisting mainly of Streptococci
macromolecules also takes place through the and Lactobacilli in quantities of 100 to 10.000 in
peritoneum, but it is not certain whether this 1 ml. The smaller the distance from the ileocecal
is through intracellular fissures in postcapil- valve, the higher the number of bacteria in the
lary arterioles or through intracellular vesicles. small intestine, so that the quantity of Streptococci
Studies in humans and animals show that in- and Lactobacillus increases to 1.000.000 to
traperitoneal blood is absorbed at a slower rate, 10.000.000 in 1 ml.
but approximately 70% enters the blood-stream.
The largest amount of pathogenic bacterial flora is
This absorption occurs primarily through the
in the colon. Of the huge number of bacteria, the
fenestration of the lymphatic channels below the
most common are anaerobic bacteria, at over 95%.
surface of the diaphragm. Such erythrocytes have
The most common of these are Streptococcus,
a normal survival time in the circulation. Air and
Bacillus species, Enteroccocci, Bifidobacteria,
gas are similarly absorbed. The air that enters the and Clostridiae. In addition to bacteria, the
peritoneal cavity during laparotomy is absorbed colon also contains fungi of the genus Candida
in 3-6 days (Makki, 2017). (Thursby and Juge, 2017).
 D E L I B E G OV I C PERITONITIS 137

Under normal circumstances, there are between and reproduction. These relationships result in the
500 and 600 different bacterial species in the gas- increased virulence of strains, and the full devel-
trointestinal tract that are in a complex symbiotic, opment of the inflammatory process. Thus, bacte-
saprophytic and parasitic relationship both with ria, which were not dominant in the intestinal lu-
each other and with the host. The stability of the men until then, begin to multiply rapidly and thus
gastrointestinal flora is maintained by a number become the main carriers of the bacterial invasion.
of factors, including competition for nutrients and Therefore, a relatively small number of bacteria
mucosal binding sites, intestinal mobility, local cause surgical infection, and only a few peritonitis.
pH, bile flow, and the production of antimicrobial This explains the fact that the most common causes
substances by intestinal epithelium and other lu- of intraabdominal infections are isolated strains of
minal organisms. If they leave their natural hab- bacteria that are not present in large numbers in the
itat and move to the peritoneal cavity, there is a normal intestinal flora (Table 1).
drastic change in these complex relationships, so
The character of the inflammatory process that
that many of the existing bacterial species, due to
takes place in the abdomen is conditioned, in
the loss of environmental conditions (intestinal
the first place, by the type of bacteria that cause
lumen), do not survive in the new conditions. By
it. Another important feature is the amount of
moving into the intraperitoneal space, bacteria face
bacteria and their virulence (Wilson et al., 2002).
the factors involved in the nonspecific defense of
Also, the pathological synergism of bacteria is
the organism, so that a large number of bacteria
important. It has been proven that severe forms of
are destroyed in contact with macrophages. This
peritonitis only develop in the presence of mixed
process leads to the harmful selection of resist-
aerobic and anaerobic flora that determine the
ant pathogenic bacteria which, freed from natural
type and character of the disease.
competition, continue their uncontrolled growth

Table 1 Bacterial cultures in patients with polymicrobial peritonitis

Aerobic bacteria

Gram-negative bacteria

Escherichia coli 60%

Enterobacter/Klepsiella 26%

Proteus 22%

Pseudomonas 8%

Gram-positive bacteria

Streptococci 28%

Enterococcus 17%

Staphylococci 7%

Anaerobic bacteria
Bacteroides 72%

Eubacteria 24%
138 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

Adjuvants sequent exposure of bacteria to systemic defense

mechanisms such as tissue macrophages, reticulo-
Many experiments have shown that certain
endothelial cells and PMN. During the initial phase
substances, referred to as adjuvants, alleviate in-
of infection, resident macrophages and, probably,
fection. These are sterile stool, barium sulphate,
fat cells, in cooperation with the clearance mech-
bile, mucus or hemoglobin. Bile, in itself, is not
anism, act as the first line of peritoneal defense
toxic, but it reduces surface tension and facilitates
to reduce the number of bacteria. This interaction
the spread of bacteria. Mucus inhibits phagocytosis
between bacteria and resident macrophages serves
by enveloping bacteria. The adjuvants’ role in
to increase the local defense response, with the
the lethality of experimental peritonitis has also
release of proinflammatory mediators that attract
been attributed to the presence of large amounts
and inform other cells, such as PMN. After the first
of fluid within the peritoneal cavity (Dunn et al.,
few hours, there is an influx of PMN into the peri-
1984). Fluid left after rinsing, during laparotomy,
toneal cavity in response to the chemotoxic stimuli
or due to ascites, may delay bacterial clearance,
released by tissue macrophages, bacterial products
enhance bacterial growth, or reduce phagocytosis
such as N-formyl peptides, and complement activa-
by diluting intraperitoneal opsonins.
tion. These cells destroy the microorganisms that
Peritoneal response to infection have penetrated and escaped other defense mech-
anisms. The pro-cess lasts for several hours and
Intraabdominal infection results from perforation
clearly coincides with the critical period during
of hollow organs leading to inoculation of bacte-
which the interaction occurs between bacterial pro-
ria into a normally sterile peritoneal cavity (Figure
liferation and the host defense mechanisms aimed
5). The normal bacterial flora found at a specific
at destroying pathogenic microorganisms. Chemo-
location in the gastrointestinal tract, determines
taxis is an important initial step, but many micro-
the initial inoculum. Some studies suggest that the
organisms, especially encapsulated ones, must be
quantity of bacteria present at the onset of intra-ab-
opsonated with a sufficient amount of specific anti-
dominal infection is higher than previously thought
bodies to be ingested. Activated C3 and IgG are the
(approximately 2 x 108CFU/ml, much more than
most important opsonins.
the routinely used 5 x 105CFU/ml inoculum for in
vitro testing). The exact events that follow the in- Macrophages are pluripotent cells that play a cen-
oculation of the peritoneal cavity with bacteria and tral role in coordinating the overall inflammato-
adjuvants of infection (blood, bile, barium sulfate), ry response. They secrete proinflammatory cy-
and the consequent translymphatic systemic spread toki-nes, such as tumor necrosis factor (TFN-α),
are the subject of further research. In animal mod- interleukin-1 (IL-1) and interleukin-6 (IL-6), which
els, when bacteria are injected into the peritoneal enhance the microbicidal properties of other
cavity, they disappear even before polymorphonu- phagocytic cells within the surrounding milieu,
clear leukocyte (PMN) influx, and can be found in and attract additional phagocytic cells to the site
diaphragmatic lymph vessels within 6 hours after of invasion and infections (Lopez et al., 2011).
injection (Hall et al., 1998). This suggests that one Macrophages also act as cells that process and
of the most important defense mechanisms of the represent components of the pathogen to T-helper
peritoneal cavity is the direct absorption of bacteria cells, resulting in activation of the adaptive im-
into the diaphragmatic lymph vessels, and the con- mune response. The final route of all these events
 D E L I B E G OV I C PERITONITIS 139

is the killing of bacteria, the elimination of for- cals, nitric oxide, cytotoxic lymphocytes, proteins
eign materials and the reestablishment of normal that increase bacterial permeability, cathepepsin,
physiology and anatomy. Bacterial killing or cyto- lactoferrin, lysosomes, proteases, lipid hydrolases
toxicity can be achieved through oxygen free radi- and kinases.

Diaphragm movement Peritoneal injury Complement activation

Mesothelial cell lysis Mast cell degranulation

Absorption through Histamine and other vasoactive Chemotaxis

diaphragmatic lymphatic lacunae substances

Vascular permeability Influx of PMN

Plasma exudation Opsonization

Reticuloendothelial system
Fibrin Phagocytosis

Localization of infection (abscess)

Destruction of bacteria

Figure 3 Pathogenesis of secondary peritonitis.

There are, however, quantitative limitations to each contaminated intestinal contents are surrounded and
of these mechanisms in dealing with contamination. the continuation of contamination of the peritoneal
Those microorganisms that avoid clearance and cavity is prevented. Fibrin itself has the ability to
phagocytosis are opposed by a final, primitive trap a large number of bacteria and also to boost
defense mechanism (sequestration) that protects the immune response. Fibrin exudate production is
the host from bacterial inoculum. The expression considered to be an important part of host defense,
of tissue factor on the surface of peritoneal but a large number of bacteria can be sequestered
macrophages initiates local activation of the within the fibrin matrix that are thus protected from
coagulation cascade, which results in fibrin deposits the action of the host clearance mechanism. This
around the inflammatory focus (Weiss and Schaible, can reduce the spread and systemic dissemination,
2015). This process serves to limit infection from and reduce early mortality from sepsis, but this
the rest of the peritoneal cavity. By acting together is also a pathway for the development of residual
with the omentum and other mobile organs, the infection and the formation of abscesses (Ordonez
perforation is closed and, as the ileus develops, the and Pouyana, 2006).
140 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

The anatomy of the peritoneum explains some After perforation and the entry of bacteria into
of the early pathophysiological changes seen the peritoneal cavity, the massive inflammatory
in intra-abdominal infection. Histamine and response includes vasodilation and exudation of
other vasoactive substances, released during the fluid, and up to 10.l of fluid can move into the
host’s defensive reaction, increase the vascular peritoneal cavity and subendothelial connective
permeability of the peritoneum. Transudation of tissue (Ordonez and Pouyana, 2006). It has
low-protein fluid from the extracellular interstitial been estimated that a 1 mm thick peritoneum
compartment into the peritoneal cavity was can sequester up to 18.l of fluid, which clearly
accompanied by the diapedesis of a large number of shows how large the fluid displacement can be
PMNs. During the early vascular and transudative in diffuse peritonitis. Atonic, dilated intestines
phases, the peritoneum is a “two-way street”, so also accumulate fluid in their lumen. Depending
that toxins and other substances, which may be in on the severity of the infection, the formation of
the peritoneal fluid, are easily absorbed, enter the inflammatory peritoneal edema may occur so
lymphatic and bloodstream, leading to systemic rapidly that it manifests clinically as hypovolemic
symptoms. Transudation of interstitial fluid into the shock. Continuous accumulation of fluid in the
peritoneal cavity, through the inflamed peritoneum, peritoneal cavity may also exacerbate bacterial
is accompanied by exudation of protein-rich fluid. phagocytosis by diluting opsonin and reducing
This exudate contains large amounts of fibrinogen neutrophil mobility and migration. At the same
and other plasma proteins in a con-centration time, gravity causes the reverse flow of fluid, so
sufficient to lead to coagulation, so that adhesions the inflamed exudate in the peritoneal cavity goes
form between the intestinal villi and other organs downward (Figure 4).
in the area of peritoneal inflammation.

Figure 4 Peritoneal fluid flow in infection.

 D E L I B E G OV I C PERITONITIS 141

Exudate basins are formed in the lower parts of the is reduced in patients who are placed in a semi-
peritoneal cavity, such as the subphrenic spaces sitting position, which is probably associated with
and pelvis (Petermann, 1927) (Figure 5). Clinical a decrease in bacterial absorption through the
observation suggests that mortality in peritonitis diaphragm (Figure 5).

Pelvic brim

Right posterior subphrenic space

Pelvic cavity Pelvic cavity

Figure 5 The influence of a semi-sitting position on absorption.

At the same time, the parietal peritoneum in the al translocation and absorption of endotoxins from
pelvis is thought to be more resistant to infection, the intestinal lumen.
due to the smaller number of lymphatic lacunae are
Sequestration of fluid within the peritoneum and
closed by cell debris and fibrin patches.
peritoneal cavity, as well as within the intestinal
The acute inflammatory process within the ab- lumen, significantly increases intra-abdominal
domen results in sympathetic activation and sup- pressure, and can cause abdominal compartment
pression of intestinal peristalsis. Fluid absorption syndrome (Hold and Agnello, 2014). Increased in-
through the intestinal wall is impaired and a sig- tra-abdominal pressure negatively affects pulmo-
nificant amount of tissue fluid can be sequestered nary, cardiac and renal function, but also hepatic
within the intestine. Reduced intestinal peristalsis planar perfusion. It may be accompanied by an in-
stimulates the growth of bacteria, and leads to the crease in intrathoracic pressure, due to respiratory
translocation of bacteria and their products from therapy or inhalation anesthesia. In combination
the intestinal lumen to regional lymph nodes, peri- with PEEP, this results in a significant increase
toneal cavity and portal circulation. Blood shunt in central venous pressure, pulmonary capillary
from the splanchnic circulation in response to wedge pressure, mean pulmonary arterial pressure
the relative hypovolemia, sequestration of fluid and pulmonary vascular resistance, and decreased
in the third space, and peripheral vasodilation in venous blood return to the heart, with changes in
response to inflammatory stimuli further compro- ventricular compliance, all accompanied by hor-
mise intestinal barrier function and affect bacteri- monal depression of cardiac function.
142 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

The course of the infection which triggers the conversion of fibrinogen to fi-
brin (Pattinson et al., 1981). Fibrin deposits are
Regardless of the mechanism of peritonitis, it
initially useful because they localize the intraperi-
goes through all the classic stages of inflamma-
toneal infection. However, a large number of bac-
tion. The primary reaction of the peritoneum
teria can be sequestered within the fibrin matrix,
to the agent begins with lysis of mesothelial
and are thus protected from the action of the host
cells and degranulation of mast cells (Figure 5).
clearance mechanism. This represents a way in
Those in the damage zone release large amounts
which abscesses are created in experimental mod-
of proinflammatory mediators into the interstitial
els (Broche and Tellado, 2001).
space. Activation of resident macrophages occurs,
and positive chemotaxis causes the transition Along with the transfer of fibrinogen from the
of PMN to the zone of inflammation. The local blood vessels, PMNs occupy a peripheral arrange-
effect of vasoactive substances is reflected in the ment in the blood vessels and begin mass migra-
vasodilation and increased permeability of the tion into the peritoneal cavity. This leads to the
small peritoneal blood vessels. In parallel with formation of pus. The pus consists of necrotic and
this process, the complement system is activated. damaged PMN, inflammatory cells, cellular detri-
Due to the action of the toxin, blood vessels are tus, causative microorganisms, and transuded flu-
paralyzed with consequent dilatation, creating a id. Regardless of the degree and type of inflamma-
pathway and the exudation of fluid. These defense tory process that takes place in the peritoneal cav-
mechanisms will cause phagocytosis of the ity, further propagation of the infectious process
bacteria, which successfully defends the organism is possible. Lymphatic openings of the peritoneum
from bacterial infection. resorb large amounts of exudates, but also bacte-
rial cells. If the macrophages do not phagocytose
If the local defense mechanisms are insufficient to
penetrating bacteria, there is a possibility of bac-
suppress the bacterial infection, the inflammato-
teria passing into the general circulation, and peri-
ry process continues and expands, and fibrinogen
tonitis is complicated by sepsis, septic shock, and
passes into the zone of inflammation or into the
the consequent development of multiple organic
free peritoneal cavity (Broche and Tellado, 2001).
The coagulation cascade, activated in the perito- dysfunction/insufficiency syndrome (Figure 6).
neal cavity, results in the formation of thrombin,

Hollow-organ perforation
Supuration Perforation Necrosis

Inoculation of bacteria into the peritoneal cavity

Means of local defense Adjuvants of infection
(omentum, lymphatic drainage) (blood, feces, necrotic tissue)
Systemic defense tools
(cellular, humoral components) Local weakness

Destruction of bacteria Localization of infection Generalization of infection

Recovery Abscess Peritonitis

Figure 6 Pathogenesis of secondary peritonitis.

 D E L I B E G OV I C PERITONITIS 143

Adhesions changes lead to a hypoxic environment in the peri-

toneal cavity, which encourages the formation of
The peritoneum heals very soon after injury. Un-
adhesions and the growth of anaerobic bacteria.
like the skin, which is completely contracted by
the wound and the centripetal growth of new epi- A normal peritoneal wound heals smoothly,
thelium from the edges of the wound, a peritoneal without the formation of adhesions. Adhesions
defect is renewed at the same time everywhere. develop in response to factors other than simple
A very large defect can heal at the same rate as peritoneal healing. Local tissue hypoxia and
a small defect. It has been experimentally proven wound ischemia are important factors in adhesion
that 3 days after a peritoneal injury, the damaged stimulation (Nauta et al., 2014). Other causes are
surface is covered with a layer of connective tissue mechanical damage to the subperitoneal surface
cells that look like mesothelial cells. On the fifth and contamination of the peritoneal surface with
day, the new surface layer looks like a normal me- foreign materials.
sothelium. On the seventh day, mesothelial regen-
eration is complete. The exact origin of these cells, Pathophysiology of intraabdominal adhesions
responsible for mesothelial regeneration, remains Peritoneal trauma results in mesothelial damage
unclear. Evidence supports a bimodal mechanism accompanied by inflammation (Herrick and Wilm,
involving the migration of mesothelial cells to the 2021). Mesothelial cells enlarge and separate from
edge of the defect, and the implantation of free, the basement membrane, creating denuded regions.
floating peritoneal mesothelial cells (PMCs) on the The inflammatory response is accompanied by
wound surface. It is also possible that pluripotent the production and release of a wide range of
cells below the mesothelium migrate to the surface biologically active proteins and the exudation of
and differentiate into PMC. Macrophages play an a proteinrich fluid. Peritoneal exudate contains
important role in mesothelial healing by inducing large amounts of fibrinogen. The coagulation
PMC proliferation (Herrick and Wilm, 2021). cascade, activated in the peritoneal cavity, results
The metabolic changes in the inflamed peritoneum in the formation of thrombin which triggers the
are similar to those that occur in dermal inflam- conversion of fibrinogen to fibrin. By activating the
mation, but they appear much faster. The synthe- fibrinolytic system, any intra-abdominal deposit
sis of membrane glycoproteins and proteoglycans can be lysed. Under normal conditions, there is a
is increased. The concentration of uronic acid is balance between fibrinolysis and coagulation.
also increased, probably reflecting the exudation Surgery, extensive and severe peritoneal injuries,
of plasma proteins in the early stages of perito- intraabdominal infection, tissue ischemia, hypox-
nitis, and in the later stages the synthesis of gly- ia, or intraperitoneal foreign bodies disturb this
coaminoglycans is increased due to the activation balance in favor of the coagulation system. Fibrin
of fibroblasts and mesothelial cells. Experimental forms deposits that are a matrix for the growth of
studies of peritoneal metabolism in peritonitis fibrocollagen tissue. Fibroblasts and capillaries
show increased oxygen and glucose consumption grow into arachnoid fibrin adhesions, followed by
and increased lactate production. There is also collagen deposits, which results in fibrous adhe-
an increase in anaerobic metabolism, mainly due sions. In addition, fibrin deposits protect bacteria
to glycolysis. Together with a decrease in partial from the immune defenses of the peritoneal cavity.
pressure and increased oxygen consumption, these
144 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

Activation of the fibrinolytic system results in the into the peritoneal cavity, as they can enhance the
conversion of plasminogen to plasmin. Plasmin inflammatory response (Gonzales-Quintero and
is highly effective in creating fibrin degradation Cruz-Pachano, 2009). Activation of the fibrinolytic
products. Plasminogen is present in high concen- system is also considered. The effect of tPA as the
trations, and only small amounts of plasminogen major plasminogen activator has been studied
activator are required to produce large amounts and, although it has shown efficacy, the risk of
of plasmin. The plasminogen activators are tissue bleeding has been a major barrier to routine use.
plasminogen activator (tPA) and urokinase plas- Antiinflammatory drugs, including corticosteroids
minogen activator (uPA). tPA is a major plasmin- and prostaglandin synthetase inhibitors, have
ogen activator and has a high affinity for fibrin. also been tested. A promising concept may be
In the peritoneal cavity, it is responsible for 95% the intraperitoneal application of hyaluronic
of plasminogen activation. Various cells produce acid, which prevents the formation of adhesions
tPA, including endothelial cells, mesothelial cells, (Vrijland et al., 2002).
and mac-rophages. Plasminogenic activity is pre-
vented by plasminogen activator inhibitors, types Inflammatory response in peritonitis
1 and 2 (PA-1, PA-2). PA-1 is a major inhibitor of Any agent, such as a bacterial endo- or exotoxin, can
tPA and uPA, and is produced by a variety of cells, initiate a series of events known as the inflammatory
including endothelial cells, mesothelial cells, mac- response (Dickinson and Lehmann, 2019). Although
rophages, and fibroblasts. PA-2 probably plays a an adequate inflammatory response provides an
role in peritoneal repair (Sulaiman et al., 2002). essential defense against infection, a reduced or
Surgery and infection in the peritoneal cavity excessive response can lead to significant morbidity
disturb the balance between coagulation and and even mortality. The inflammatory response is
fibrinolysis. In peritoneal fluid, fibrinolytic activity the end product of the complex interaction between
is reduced mainly due to the increase in PA-1. cellular and humoral components (Figure 7). The
Therefore, PA-1 is considered an important factor humoral components are molecules that circulate in
in the development of adhesions. It is also of great the body, including antibodies and the complement
importance that PMCs have a predilection to grow system, quinines, lipid mediators, and acute phase
within blood clots, emphasizing the potent role of cytokines.
blood clots in adhesion formation. This explains Cellular components consist of granulocytes,
why adhesions are thickest when two denuded mononuclear phagocytes, lymphocytes and vari-
surfaces are joined to coagulated blood. Adhesion ous non-leukocyte cells that affect many processes
formation is a protective mechanism that helps during inflammation. Microscopically, these cel-
localize peritoneal stroke, but also an adaptive lular and humoral elements lead to changes in the
response that helps bring additional blood supply local vascular network mediated by quinines, cyto-
to the ischemic injured region of the peritoneum. kines, chemokines, lipid mediators, neuropeptides,
reactive oxygen species, and nitrogen products.
Adhesion prevention
Within 30 to 60 minutes, neutrophils marginalize,
Prevention of the formation of adhesions after extravasate, and accumulate at the site of inflamma-
surgery focuses on minimizing peritoneal trauma tion, where they ingest pathogenic microorganisms
and reducing the introduction of foreign materials and release oxidants and proteases (Rosales, 2018).
 D E L I B E G OV I C PERITONITIS 145

ENDOTOXIN LIPOPROTEINS LTA FLAGELLIN

KININ-KALLIKREIN SYSTEM FIBRIONOLYSIS COAGULATION COMPLEMENT SYSTEM

IL-6 Factor XII C5a C3a

Acute IL-1 Activated macrophages
phase TFN
proteins
T helper lymphocyte

Microorganisms Antibodies
B lymphocyte

Elimination of microorganisms

Figure 7 Inflammatory response in peritonitis.

Within 4 to 5 hours, mononuclear cells (monocytes high microbicidal capacity, are found within the
and lymphocytes) begin to accumulate at the site of bloodstream but in small numbers in tissues. They
inflammation. The attracted monocytes and resident are mobilized to the extravascular site of infec-
macrophages participate in nonspecific phagocytic tion via diapedesis in response to the chemotactic
activity, while lymphocytes initiate specific, anti- stimuli released by tissue macrophages, bacterial
body-dependent cell lysis. breakdown products such as N-formyl peptides,
and complement activation. This process lasts for
Cellular components several hours and coincides with the critical peri-
A large number of different cells on several levels od during which the interplay of bacterial prolif-
serve as the host’s defense. As already mentioned, eration and reduction of infection due to the host
during the initial phase of infection, macrophage response occurs (Durum and Rotstein, 2001).
residents act as the first line of peritoneal defense Local activation of defense mechanisms can also
against infection and participate in the initial have a detrimental effect on the host. Secretion of
clearance of pathogenic microorganisms through lysosomal enzymes (cathepsin, elastase), free radi-
phagocytosis. Macrophages also act as antigen- cals (superoxides, hydroxyl), nitric oxide and cyto-
processing cells and present them to the T-helper kines secreted by macrophages and PMN can dam-
cells, thus initiating an immune response. age neighboring cells, but also lead to tissue damage
Macrophages are pluripotent cells that play a cen- far from the site of infection. Systemic activation
tral role in coordinating the overall inflam-matory of the inflammatory response can induce excessive
response. Through their interaction with microor- activation of circulating immune cells, as well as
ganisms, these cells are activated, with the creation those in distant organs, resulting in organ damage
of a wide range of mediator molecules capable of and the development of multiple organic dysfunc-
numerous immune functions. Thus, for example, tion/insufficiency syndrome (MODS/MOF).
polymorphonuclear leukocytes (PMNs), cells with
146 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

Early response cytokines Immune functions affected by these polypeptides

include the host’s response to acute and chronic
Cytokines are low molecular weight polypeptides
bacterial, viral, fungal, parasitic infection, trauma,
secreted after initial activation of macrophages or
burns, allograft rejection, ischemicreperfusion
lymphocytes, and may themselves act on the cells
injury, and autoimmune diseases. They play an
that secrete them (autocrine activation), or on other
important role in tumor biology and angiogenesis.
cells within the same milieu (paracrine stimulation),
Excessive cytokine release is responsible for the
and increase the secretion of the same or other
development of acute respiratory distress syndrome
cytokines. They have a wide range of actions at
(ARDS) and MOF. Their various actions and effects
both the local and systemic levels. They play an
are numerous. The most important cytokines are tu-
important role in regulating the immune response,
mor necrosis factor-α (TFN-α), interleukin-1 (IL-1)
and act in different ways on T and B cells, monocyte-
and interleukin-6 (IL-6) (Moshage, 1997, Sakashita
macrophage line cells, neutrophils, fibroblasts,
et al., 2000).
smooth muscle cells, endothelial and epithelial cells.

Table 2 Effects of early response cytokines

Source Monocytes/ macrophages, Monocytes/macrophages, Monocytes/ macrophages,

keratinocytes, Kupffer keratinocytes, Kupffer cells, keratinocytes, Kupffer cells,
cells, fibroblasts, astrocytes, fibroblasts, endothelial fibroblasts, endothelial
glial cells, fat cells, NK cells, astrocytes, microglial cells, astrocytes, PMN,
cells, T and B lymphocytes cells, epithelial cells, PMN, microglial cells, T and B
vascular smooth muscle lymphocytes, epithelial
cells, epithelial cells, NK cells.
cells, T and B lymphocytes

Rise in body temperature ++ +++ +

Shock induction +++ ++ +/-

Stimulation of the acute phase of

+ ++ +++
the response

Endothelial cell activation +++ ++ +/-

Procoagulant activity +++ ++ +/-

Anorexia, weight loss +++ ++ +/-

Fibroblast proliferation ++ ++ -

NK - natural killer cells

 D E L I B E G OV I C PERITONITIS 147

Anti-inflammatory cytokines colitis or Crohn’s disease. Preliminary clinical

findings show the benefits of IL-10 therapy,
Although generally considered proinflammatory,
suggesting that these diseases may be the result
cytokines may also have antiinflammatory effects,
of a disturbed balance of proinflammatory and
and are important in regulating the overall inflam-
antiinflammatory cytokines.
matory response. The main anti-inflammatory cy-
tokines are IL-4, IL-10, IL-13 and TGF-γ (Badiu et Interferons
al., 2011). These molecules were discovered due to
their ability to inhibit the production of TFN-α in Interferons are unique because they possess potent
LPS-stimulated macrophages. Blockade of any of antiviral and antitumor properties. They are divided
these leukins increases TFN-α levels and attracts into type I (IFN-α, INF-β) and type II (IFN-γ)
neutrophils. The IL-1 receptor antagonist (IL-1ra) interferon (Weighardt et al., 2006). Type I interferon
is a product of stimulated macrophages and also a can be produced by any cell when properly stimulated.
counterregula-tory factor in the inflammatory re- Viruses are the most potent inducers of IFN-α and
sponse. These cytokines antagonize proinflamma- INF-β (Nagarajan, 2011), but also LPS, double-
tory effects by increasing IL-1ra and soluble TFN stranded RNA, IL-1 and TFN-α. IFN-α, and INF-β
receptors. IL-4, IL-10, IL-13 are produced by the regulate the expression of MHC class I molecules.
Th2 subclass of helper T cells and share many sim- They also stimulate B cell development and the
ilar effects. The procoagulant state of inflamma- proliferation and change of IgM immunoglobulin
tion is reduced by their inhibition of LPS-induced heavy chains to IgG. Type I interferon inhibits cell
tissue factor activity. IL-4, IL-10, IL-13 inhibit the replication of normal and tumor cells, and enhances
induction of COX-2 and iNOS in monocytes and NK cell activity. Type II interferon is only produced
macrophages. by T cells and activated NK cells. IFN-γ is a major
activating factor for macrophages. It regulates the
Interleukin-10 appears to be the most potent anti- expression of MHC class II and class I molecules. It
inflammatory cytokine in this group (Kato et al., is involved in reciprocal stimulation with TFN and
1995). It is secreted predominantly by monocytes IL-12. Stimulated macrophages activate NK cells
and macrophages, and by T and B lymphocytes. by releasing TFN and IL-12, and these activated NK
IL-10 production is increased by exposure to LPS, cells then release IFN-γ, which further stimulates
TFN-α, IL-4, IL-13. IL-10 reduces the syn-thesis macrophages to secrete more TFN and IL-12. IL-12
of TFN-α, IL-1, IL-6 and IL-8 in monocytes and released from monocytes and macrophages activates
macrophages. IL-10 also stimulates the release of Th1 cells while inhibiting the TH2 subclass. IFN-γ
other anti-inflammatory molecules, specifically induces the release of IL-1 and IL-6 and, together
soluble TFN-α receptors and IL-1ra. Serum IL- with TFN and IL-6, may act synergistically to
10 levels are often elevated in burns, injuries, mediate cytotoxicity. IFN-γ stimulates the attraction
sepsis, ARDS and MOF. According to some of inflammatory cells and enhances microbicidal
studies, patients with the highest levels of IL- activity in macrophages and neutrophils.
10 died (Emparan and Senninger, 2000). It is
unclear whether this is a pathological response or During the initial activation of macrophages, in re-
a marker of the severity of the damage. The IL-10 sponse to bacterial products, interferon-γ (IFN-γ)
molecule may be important in the development of is released by T cells and IL-1 by macrophages
inflammatory bowel diseases, such as ulcerative (Ivashkiv, 2018). The secretion of IFN-γ and IL-1
148 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

may be accompanied by the secretion of TFN-α Overall, antibodies and complement work together
by macrophages, followed by the secretion of IL-6 to neutralize microbial toxins, lyse pathogenic mi-
and other cytokines. In experimental models, IL-1 croorganisms, and/or significantly enhance phago-
is capable of producing fever, hypotension, while cytosis of those microorganisms that have avoided
TFN-α causes fever, hypotension, intestinal isch- initial neutralization and lysis. At the same time,
emia, and death. Approximate-ly 1.5 to 2 hours after fragments of some complement components at-
lipopolysaccharide (LPS) administration, IL-1 and tract additional cellular defense components and
TFN-α are produced, followed by IL-6 and IL-8 se- direct them toward the area of infection.
cretion (Kumolosasi et al., 2014).
The coagulation cascade also plays an important
The duality of the effects of cytokines on the host role in the local and systemic inflammatory re-
itself is becoming more and more important. In sponse (McGilvray and Rotsein, 1998). This pro-
experimental models, the application of TFN or cess of immune coagulation is mediated by mol-
IL-1 strengthens the host’s defenses, but the initial ecules on the cell surface, such as tissue factor,
application of high doses leads to death. As noted, plasminogen activator and plasminogen activator
excessive activation of local defenses may result in inhibitors, which to some extent used to deter-
cytokine entry into the systemic circulation. This mine the balance between procoagulant response
process is most likely to explain the occurrence and anticoagulant/fibrinolytic activity. In general,
of a “septic condition” or systemic inflammatory infection and inflammation induce a procoagulant
response syndrome (SIRS) in patients in whom no response by increasing molecules such as tissue
active infection can be identified. factor and plasminogen activator inhibitors on
monocytes/macrophages and endothelial cells and
Humoral components overall lead to decreased plasminogen activator
Stimulation of the immune system occurs after activity. This insurance of fibrin deposits encour-
different cells present processing antigens (macro- ages local inflammation due to the potent immu-
phages, B lymphocytes, dendritic cells, Langerhans nomodulatory effects of its breakdown products.
cells) to T-helper cells (Chaplin, 2010). These T However, this can also contribute to damage to
lymphocytes stimulate B lymphocytes that bec- distant organs through the induction of microvas-
ome mature plasma cells with the production of cular thrombosis.
antibodies directed against specific antigens. At
the same time, complement cascade activation by Integration of inflammatory components
certain antibodies occurs. However, many other The acute phase response is characterized by
substances are able to activate the complement changes in liver metabolism, activation of the
cascade directly, in a classical or alternative way. central nervous system, leading to fever and
Thus, for example, Gram-negative microorganisms adaptive behavior, altered hematological profile,
are able to activate one or both pathways, while many activation of the complement, fibrinolysis and
fungi activate the alternative pathway directly. The coagulation cascades, and release of neuropep-
complement cascade is a relatively primitive host tides, quinine and hormones (Grys et al., 2005). It
de-fense mechanism that is extremely effective is a rapid, nonspecific response that occurs before
in preventing infection, especially when acting in a specific immune response. Cytokines are the
conjunction with other components of the defense main mediators of the acute phase response, and
system. IL-6, IL-1 and TFN-α play a central role.
 D E L I B E G OV I C PERITONITIS 149

Acute phase proteins are proteins whose glucocorticoids may act together with glucagon
concentration increases by at least 25% during and epinephrine to increase blood glucose levels
in-flammation. They begin to grow after a delay during the acute response phase. Metabolic changes
of approximately 6 hours, and serve to establish include altered lipid status and negative nitrogen
homeostasis after infection or inflammation. balance. Plasma levels of zinc and iron decrease,
These include haemostatic functions (fibrinogen), and copper levels increase. This decrease in zinc
microbicidal and phagocytic functions (comple- and iron levels is accompanied by a decrease in
ment components, CRP), antithrombotic properties plasma binding proteins (transferrin and albumin).
(α1-acid glycoprotein, plasminogen), antioxidant Low levels of these metals can have a protective
properties (haptoglobulin, hemopexin) and effect, as they are essential for microbial growth.
antiproteolytic properties, α1-α1-α2-α2-inhibitor Bacterial products, such as LPS, are the most
protease and α2-antichymotrypsin). The size potent activators of the tissue macrophages that
of the response depends on the severity of the initiate the acute phase response. LPS, through
stress and varies from patient to patient. Systemic interaction with the LPS binding protein, CD14
manifestations include neuroendocrine changes, and Toll-like receptors, induces the synthesis of
changes in hematological profile, and metabolic and free radicals and reactive oxygen species including
chemical changes. The classic neuroendocrine man- NO, lipid derivatives such as PGE2, thromboxane
ifestation is a rise in body temperature. IL-1, IL-6 A2, FAT and acute phase cytokines.
and TFN mediate by acting on the hypothalamic
center through PGE2 synthesis. Secretion of Monitoring the inflammatory response
neuropeptides, such as arginine vasopressin (AVP), Many parameters change during an infection.
and corticotropin-releasing hormone (CRH), and These include cytokines, mainly secreted from
hormones, such as glucagon, insulin, thyroxine, monocytes (IL-1, IL-6, IL-8, IL-10, IL-18 and
and aldosterone, is also characteristic in the acute TFN-α), functional changes in granulocytes
phase of the response. CRH and AVP released in (chemotaxis, phagocytosis, oxygen radical form-
the hypothalamus increase ACTH and cortisol ation), histamine release from fat cells, NO
levels. An increase in cortisol levels is one of the expression and adhesion of molecules to endothelial
earliest signs of systemic changes. The release of cells, release of coagulation factors, complement
cortisol inhibits the rise in temperature and the factors, adhesion of molecules and procalcitonin
gene expression of cytokines, contributing to its (PCT) from epithelial cells (Attia et al., 2012).
potential regulatory function in the acute phase of These changes produce biological effects, such
the response. as fever, metabolic disorders, dilation of blood
Glucocorticoids increase the synthesis of some vessels, capillary permeability, and disseminated
acute phase proteins involved in connective tissue intravascular coagulation.
repair and coagulation (fibrinogen), as well as The biological effects lead, in severe cases, to the
antioxidants and antiproteinases (haptoglobin and classical clinical indicators that are routinely mon-
α2-macroglobulin) (Russo-Marie, 1999). They itored during infection, including: decreased car-
may also function as a counterbalance to the diac output, hypotension, hypovolemia, intestinal
hypoglycaemic response due to excessive insulin edema, and multiple organ dysfunction.
production during infection or stress. In this way,
150 Veterinaria Vo l . 7 1 • I s s u e 2 • 2 0 2 2

Therapeutic decisions are based on monitoring the Catecholamines, antimicrobials, analgesics, nar-
patient’s inflammatory status. Common laboratory cotics, histamine antagonists, anticoagulants,
parameters, such as leukocyte count and C-reactive calcium channel blockers and various other drugs
protein, are nonspecific to distinguish between can affect the level of cytokines in the blood.
bacterial and nonbacterial infection. They manifest Also, well-known risk factors for adverse surgery
late, when clinical signs are already evident. outcome, such as old age and trauma, gender and
genetic predisposition, may modulate cytokine
Monitoring parameters expression. It is necessary to think about these
Of the potential markers, the highest predictive complex interactions when interpreting findings
value for the development of sepsis is found in IL-6 (Chen et al., 2018).
and procalcitonin. SIRS generally correlates with
an increase in PTC levels greater than 3 ng/ml, and
IL-6 more than 98 pg/ml, while sepsis results in CONCLUSION
levels greater than 16 ng/ml for PTC and 380 pg/ml
Host defense during peritonitis is extremely com-
for IL-6. The easiest way to measure cytokines is to
plex, due to the interaction that occurs between dif-
use peripheral venous blood. The assay is performed
ferent forms of host defense. Two important issues
using a commercial immunoassay such as ELISA
need to be emphasized: a) while the individual host
and RIA (Zhou et al., 2010).
acts as a series of barriers to infection, many de-
fense components can act in tandem and/or syner-
Clinical factors that may alter the inflammatory
gistically to prevent infection, b) many host defense
response
components can have a destructive effect on the
Major surgery is associated with an increase in host; so that an excessive response alone can cause
circulating TFN-α and IL-6 on the first day after organ damage and the development of multiple or-
surgery, and with a return to normal levels in ganic dysfunction/insufficiency syndrome.
the absence of infection the day after. In most
cases, PCT does not increase after surgery, but it
seems to be more specific for detecting infection. CONFLICT OF INTEREST
Anemia induces a decrease in the production
of proinflammatory cytokines, which is further The author has no conflict of interest.
enhanced by blood transfusions, resulting in a
worsened response to infection. Malnutrition is also
associated with significant immunosuppression,
characterized by atrophy of lymphoid organs,
impaired cellular immunity, and an increased
risk of viral and opportunistic infections. Hyper
and hypoglycemia are associated with inhibition
of IL-1 synthesis and release from macrophages.
The kidneys play a role in cytokine metabolism
and clearance. Cytokine expression and release
are also altered by pharmacological interventions.
 D E L I B E G OV I C PERITONITIS 151

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PATOFIZIOLOGIJA PERITONITISA

SAŽETAK

Peritonitis označava upalu peritoneuma, čiji uzrok nije specifičan. Može se smatrati lokalnim
ekvivalentom sistemskog upalnog odgovora koji se vidi nakon bilo kojeg pokretača upale i naziva se
sindromom sistemskog upalnog odgovora (SIRS). Peritonitis se odvija zajedno s mnogim, složenim
patofiziološkim promjenama na sistemskom i ćelijskom nivou.
Ključne riječi: Adhezija, citokini, peritonitis, PMN