The role of CCL3/macrophage inflammatory protein-1α in experimental colitis
Introduction
There is much evidence to suggest an essential role for neutrophils in tissue ulceration and inflammation during inflammatory bowel disease including Crohn's disease and ulcerative colitis (Anezaki et al., 1998, Izzo et al., 1992, Panes and Granger, 1998). For instance, a number of clinical studies have reported increased neutrophil accumulation in rectal biopsies of patients with active inflammatory bowel disease compared to healthy controls (Anezaki et al., 1998, Izzo et al., 1992, Panes and Granger, 1998). Furthermore, a series of animal studies have associated colonic neutrophilia with acute colitis (Galvez et al., 2000, McCafferty et al., 1994). However, in the last couple of years, a number of studies have also provided evidence suggesting that colonic neutrophil accumulation does not contribute to the progression of colonic injury during acute colitis (Buell and Berin, 1994, Wallace et al., 1998, Yamada et al., 1991). As a result, in recent years, much effort has been focussed on characterising the role played by endogenous mediators in promoting neutrophil recruitment during active inflammatory bowel disease.
Chemokines constitute a family of small (∼8–15 kDa) structurally related proteins that are widely regarded as one of the most important regulators of leukocyte trafficking and activation during the inflammatory process (Baggiolini, 1998, Luster, 1998). The CC chemokine CCL3/macrophage inflammatory protein (MIP-1)-1α is a potent neutrophil chemoattractant in vivo, with increases in its expression associated with the progression of tissue injury and inflammation during enteritis (Morteau et al., 2002), allergic inflammation (Das et al., 1999), sepsis (Standiford et al., 1995), hepatitis (Ajuebor et al., 2004a, Ajuebor et al., 2004b) and lung injury (Smith et al., 1994). The notion that CCL3/MIP-1α could contribute to the pathogenesis of inflammatory bowel disease stems from a number of clinical studies in which rectal biopsies of patients with active ulcerative colitis or Crohn's disease were observed to highly express CCL3/MIP-1α relative to controls (Banks et al., 2003, Vainer et al., 1998). Furthermore, studies by Banks et al. (2003) and Grimm et al. (1996) showed that the expression of CCL3/MIP-1α correlated with the severity of colonic inflammation. However, the contribution of CCL3/MIP-1α to the pathogenesis of inflammatory bowel disease remains undefined (Sun et al., 2001).
The present study assessed the role of CCL3/MIP-1α during trinitrobenzene sulfonic acid-induced colitis in rats.
Section snippets
Animals
Male Wistar rats (175±20 g) were purchased from Charles River Breeding Farms Limited (Montreal, Canada). The animals were fed a standard chow pellet diet, had free access to water and were maintained on a 12-h light/dark cycle. All procedures were approved by the Animal Care Committee of the University of Calgary and were performed in compliance with the guidelines of the Canadian Council on Animal Care.
Induction of colitis
Rats were lightly anaesthetized with halothane and the hapten TNBS (60 mg/ml in 0.5 ml of
Time course of neutrophil accumulation
In agreement with previous reports, intracolonic administration of a single dose of TNBS caused significant increases in neutrophil accumulation in the colon as demonstrated by a striking increase in MPO activity at 24 h (18-fold increase above control; P<0.01), day 3 (22-fold increase above control; P<0.01) and day 7 (10-fold increase above control; P<0.05) post-TNBS administration (Fig. 1A). It is noteworthy that the MPO activity at day 7 post-TNBS treatment was significantly (P<0.05) reduced
Discussion
The pathological association between leukocytes and inflammatory bowel diseases including Crohn's disease and ulcerative colitis has long been recognized. Neutrophils are known to play a crucial role in the pathogenesis of inflammatory bowel diseases (Panes and Granger, 1998). However, despite tremendous progress in our understanding of the pathophysiology of inflammatory bowel diseases, several key questions remain unresolved. First and foremost, the mechanisms governing neutrophil migration
Acknowledgements
This work was supported by a grant from the Canadian Institute of Health and Research (CIHR). Maureen N. Ajuebor was supported by a Canadian Association of Gastroenterology/Schering/CIHR post-doctoral fellowship.
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