Objective

Acute respiratory distress syndrome (ARDS) is a life-threatening condition associated with a high rate of mortality. The only effective treatment option is supportive ventilator therapy. ARDS is characterised by disruption of the alveolar endothelial/epithelial barrier, oedema and the excessive accumulation of neutrophils. Crucially, neutrophils are thought to contribute to the bystander tissue damage associated with ARDS. IL-8 (CXCL8) has long been considered to be the conventional neutrophilic chemokine. However, we have now demonstrated in a mouse model of LPS-induced acute lung injury that inhibiting CCL2 or CCL7 significantly reduced neutrophil recruitment. BAL fluid neutrophils expressed higher levels of the chemokine receptor CCR2, and lower CXCR2, compared to those from blood, indicating differential chemokine receptor expression. Mice infected with the bacterium Streptococcus pneumoniae had elevated CCL2 and CCL7 levels, while inhibiting CCL7 also reduced neutrophil recruitment. In addition, CCL2 and CCL7 were both chemotactic for human neutrophils, while inhibiting either CCL2 or CCL7 significantly reduced the chemotactic activity of ARDS BAL fluid. Furthermore, CCL2 and CCL7 synergised with IL-8 in order to promote neutrophil migration. These comprehensive studies reveal that CCL2 and CCL7 may be appropriate targets to reduce excessive neutrophil recruitment in ARDS.