Role of adhesion molecule ICAM in the pathogenesis of polymicrobial sepsis

Introduction: Intercellular adhesion molecule-1 (ICAM-1) is thought to be involved in polymorphonuclear leukocytes (PMNL) recruitment and secondary organ damage in response to infection and inflammation. The precise role of ICAM-1 in disease progression is unknown and remains a topic of controversy. The aim of this study was to investigate the effect of ICAM-1 on histological changes and cytokine synthesis in a murine model of polymicrobial sepsis. Methods: Polymicrobial sepsis was induced in experimental animals by caecal ligation and puncture (CLP). A control group was formed using sham laparotomy without CLP. In order to ascertain the role of ICAM-1 in the response, procedures were performed in both ICAM-1 knockout animals (ICAM-1^-/-) and in C57BL/6 mice that were not genetically modified (wild type, WT). Clinical response was observed daily, morphological changes occurring in the lung and liver were studied using light microscopy and quantified using a scoring system. Plasma concentrations of various cytokines (TNF-α, IL-6, IL-10) were measured via ELISA. Results: In ICAM-1^-/- mice a less severe clinical response to induced sepsis was observed with significantly less weight loss and hypothermia. A significantly lower mortality rate was observed in ICAM-1 ^-/- mice (12.5% vs. WT: 45.5%) and no significant histological changes were apparent in pulmonary or hepatic tissue on light microscopy following CLP. In WT animals however, significant evidence of leukocyte infiltration and interstitial thickening in pulmonary tissue was observed. Similarly, hepatic tissue sinusoidal widening and hydropic degeneration was present. In addition, pro- and anti-inflammatory cytokine synthesis in ICAM-1^-/- animals was significantly attenuated when compared to WT mice. (ICAM-1^-/-: TNF-α: 67.7±12.1 pg/μl; IL-6: 208.9±26.7 pg/μl; IL-10: 34.6±5.8 pg/μl; WT: TNF-α: 840.7±150.2 pg/μl; IL-6: 3100.2±1052.3 pg/μl; IL-10: 1550.1±495.7 pg/μl). Discussion: This study suggests that ICAM-1 has an important pathophysiological role in the response to polymicrobial sepsis. It would appear that absence of this molecule impairs the ability of PMNL to migrate into organ tissues and reduces consequent secondary organ damage resulting in improved clinical status and overall survival. Further investigation into the effectiveness of ICAM-1 modulation in the treatment of sepsis is warranted.