Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury.

The aim of the present study was to evaluate the effects of the CC chemokine receptor (CCR) 2b and CCR1 antagonist RS504393 as well as the roles of CCRs on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In A549 cell line, treatment with RS504393 significantly inhibited the expression of CCR1, CCR2 and interleukin (IL)-8 after either LPS or tumor necrosis factor-alpha stimulation. An ALI model with intranasal LPS administration was used on C57BL/6J, CCR1, CCR2 and CCR3 knockout mice. Treatment with RS504393 had a noteworthy preventative effect on LPS-induced over-expression of IL-1beta, plasminogen activator inhibitor and CCR2. In CCR1 and CCR2-deficient animals, LPS-induced less increase of lung weight, bronchoalveolar lavage (BAL) leukocytes and IL-6 compared to the C57BL/6J and CCR3 knockout mice. This was most prominent in the CCR2 knockout mice where no LPS-induced lung edema and no increase of IL-6 in BAL fluid occurred. Our results indicate that CCR2, and to some extent CCR1, play pivotal roles in the development of ALI.