Role of adhesion molecule ICAM in the pathogenesis of polymicrobial sepsis
Introduction
A major cause of the inflammatory response, resulting in multiple organ failure in critically ill patients, is systemic sepsis. A crucial pathophysiological step in this inflammatory response is the adherence of polymorphonuclear leukocytes (PMNL) to capillary endothelial cells (Eppiheimer and Granger, 1997). Adherence enables the activated PMNL to release oxygen free radicals and proteases (McIntyre et al., 1997) leading to subsequent endothelial injury and resulting in increased capillary permeability and interstitial oedema. Furthermore, migration and extravasation of the PMNL induces further production of proteases and reactive oxygen species, leading to further organ damage and dysfunction. It has been observed that, having one of the largest endothelial beds, the lung is commonly one of the first organs to fail under such circumstances, followed by the liver.
Recently, much research interest has been directed towards the molecular basis of inflammation, including the structure of cell surface receptors involved in signal transduction and cellular adhesion. It has been ascertained that PMNL adherence apparently occurs in three steps. Initially, PMNL interact transiently with endothelial cells, resulting in characteristic “rolling” over the endothelium, a process mainly mediated by the selectins (Ridings et al., 1995; Rosen and Bertozzi, 1994; Tedder et al., 1995). The second step, firm adhesion, is mediated by Intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell (Seekamp et al., 1993; Tedder et al., 1995) and integrins (CD18/11) on the PMNL (Walsh et al., 1991). It has been suggested that ICAM-1 may also be involved in selectin-mediated PMNL rolling (Steeber et al., 1999). The final step involves PECAM-1 and results in extravasation of PMNL and ultimate migration into the tissue.
ICAM-1 is continuously expressed on the endothelium at low levels. During infection and inflammation, expression is profoundly up-regulated within 6–8 h of the initial insult (Steeber et al., 1999). In particular, significant up-regulation during sepsis and LPS stimulation, resulting in an increased PMNL-endothelial cell adhesion, has been observed (Beck-Schimmers et al., 2002). It has also been demonstrated that cell bound ICAM-1 can be released from the surface and become soluble (termed “shedding”). Increased plasma levels of soluble ICAM-1 (sICAM-1) therefore indicate systemic endothelial activation. Various different patterns of sICAM-1 release have been observed in different clinical scenarios. Taking trauma and sepsis as examples, high levels are recorded in septic shock, intermediate levels in severe sepsis and no changes during traumatic hemorrhagic shock (Boutiere et al., 2002). It appears that sICAM-1 levels are associated with the severity of sepsis.
Interactions between adhesion molecules and proinflammatory cytokines have also been described. It has been demonstrated that ICAM-1 expression can be stimulated by proinflammatory cytokines (Welthy-Wolf et al., 2001), leading to granulocyte adhesion and activation (Tedder et al., 1995). A possible regulatory role of ICAM-1 for cytokine production has also been described (Welthy-Wolf et al., 2001).
Despite these findings, the specific role of ICAM-1 in disease (e.g. sepsis) progression and cytokine regulation remains unclear. Therefore, any potential for therapeutic immune modulation utilising ICAM-1 blockade remains speculative (Katja et al., 2001). Animal models of infection and acute lung injury have highlighted the importance of ICAM-1 in the inflammatory process. Administration of monoclonal anti-ICAM-1 antibodies or the use of ICAM-1 knockout animals (ICAM-1−/−) resulted in decreased PMNL migration into inflammatory sites (Doerschuk et al., 1996; Kumasaka et al., 1996; Mulligan et al., 1993). However, these results have been inconsistent and other studies have failed to demonstrate reduced PMNL accumulation in sites of inflammation during LPS-induced infection when using ICAM-1 knockout mice or after administration of ICAM-1 antibodies (Raeburn et al., 2002; Welthy-Wolf, et al., 2001).
In an attempt to further understand the role of ICAM-1 in severe infection, we undertook an animal study using a mice model of polymicrobial sepsis. The effect of ICAM-1 on histological changes in specific organs following induction of sepsis was investigated. In addition, the influence of ICAM-1 on clinical course, mortality and plasma cytokine concentrations (TNF-α, IL-6 and IL-10) were also observed.
Section snippets
Animal care
Prior to initiation, the study was fully approved by the animal welfare committee of the state of lower Saxony. Experiments were performed in 18 male C57Bl/6 ICAM-1 knockout (ICAM-1−/−) mice aged 8–10 weeks and weighing 22±3 g. Twenty-one male C57Bl/6 mice of similar weight without receptor knockout (wildtype; WT) were used as a control group. The animals were bred and raised under pathogen free conditions in the central animal facility of our institution. Throughout the study period, pelleted
Survival rates
All sham-operated animals survived the experimental procedure until sacrifice at 96 h. In the C57B1/6 ICAM-1−/− group undergoing CLP, a single animal died at 48 h with the remainder surviving until sacrifice (mortality rate: 12.5%). In the WT CLP group, 5 out of 11 animals died (mortality rate: 45.5%) () (Fig. 1).
Body weight
Before the experiment, body weight ranged from 21 to 23 g. Average weight loss in sham-operated mice was 2.1±0.1 g over the first 24 h post-operatively. Thereafter, body weight
Discussion
Endothelial binding of PMNL is a critical contributor to the changes in vascular permeability and subsequent tissue damage observed in systemic septic insults and is regulated by endothelial cell adhesion molecules such as ICAM-1 (Dixon et al., 2004). This study investigated the effects of ICAM-1 on mortality, temperature, weight loss, cytokine concentrations and changes in pulmonary and hepatic histology in a mouse model of polymicrobial sepsis.
The main results of this study can be summarized
Conclusion
In the present study, we found further evidence that ICAM-1 plays an important role in the pathophysiological events leading to adverse outcome after polymicrobial sepsis. The absence of this adhesion molecule had protective effects against PMNL infiltration and subsequent interstitial thickening of the lung. Furthermore, ICAM−/− mice had no significant signs of PMNL infiltration, hydropic degeneration and sinusoidal widening of the liver. This was associated with improved survival rates in
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