Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology

Resolution of severe Respiratory Syncytial Virus (RSV)-induced bronchiolitis is mediated by alternatively activated macrophages (AA-M phi) that counteract cyclooxygenase (COX)-2-induced lung pathology. Herein, we report that RSV infection of 5-lipoxygenase (LO)(-/-) and 15-LO-/- macrophages or mice failed to elicit AA-M phi differentiation and concomitantly exhibited increased COX-2 expression. Further, RSV infection of 5-LO-/- mice resulted in enhanced lung pathology. Pharmacologic inhibition of 5-LO or 15-LO also blocked differentiation of RSV-induced AA-M phi in vitro and, conversely, treatment of 5-LO-/- macrophages with downstream products, lipoxin A(4) and resolvin E1, but not leukotriene B-4 or leukotriene D-4, partially restored expression of AA-M phi markers. Indomethacin blockade of COX activity in RSV-infected macrophages increased 5-LO and 15-LO, as well as arginase-1 mRNA expression. Treatment of RSV-infected mice with indomethacin also resulted not only in enhanced lung arginase-1 mRNA expression and decreased COX-2, but also decreased lung pathology in RSV-infected 5-LO (/) mice. Treatment of RSV-infected cotton rats with a COX-2-specific inhibitor resulted in enhanced lung 5-LO mRNA and AA-M phi marker expression. Together, these data suggest a novel therapeutic approach for RSV that promotes AA-M phi differentiation by activating the 5-LO pathway.