Kouji Matsushima

IL-8 in Animal Models of Disease

Inflammatory reactions are characterized by dramatic movement of leukocytes and fluids from the bloodstream into the inflamed tissues. The classical chemotactic factors such as C5a, leukotriene B4 (LTB4), and platelet-activating factor (PAF) mediate the migration of all types of leukocytes. However, pathologically, it is well known that the types of infiltrating cells vary depending largely upon the stimuli and the interval from the injury. Neutrophils infiltrate at early phase of the inflammation and are hallmarks of acute inflammation, whereas macrophages, lymphocytes and plasma cells are main components of chronic inflammation that follows the acute inflammation if the causal stimuli are not removed. The existence of specific chemotactic factor for the selective recruitment of leukocytes has been postulated for a long time.

Chemokine, as a target to intervene inflammation.

Glomerular infiltration by neutrophils is a hallmark of acute glomerulonephritis. The pathophysiological role of interleukin-8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), was explored in an animal model of acute immune complex-mediated glomerulonephritis by administering a neutralizing antibody against IL-8. Repeated injection of bovine serum albumin (BSA) into rabbits caused the deposition of immune complexes consisting of BSA and rabbit IgG in glomeruli. Histological analyses revealed a small but significant number of neutrophils in glomeruli and the fusion of epithelial cell foot processes. Concomitantly, urinary levels of protein and albumin increased markedly (3.20±0.97 and 1.39±0.53 mg/hr, respectively) compared with those of untreated animals (0.77±0.21 and 0.01±0.01 mg/hr, respectively) . Anti-IL-8 antibody treatment decreased the number of neutrophils in glomeruli by 40% and dramatically prevented the fusion of epithelial cell foot process. Furthermore, treatment with anti-IL-8 antibody completely normalized the urinary levels of protein and albumin (0.89±0.15 and 0.02±0.01 mg/hr, respectively) . These results indicated that IL-8 participated in the impairment of renal functions in experimental acute immune complex-mediated glomerulonephritis through activating as well as recruiting neutrophils. Here, we will overview the roles of chemokine in human diseases and discuss our therapeutic approaches to intervene inflammation targeting chemokine.