Alveolar macrophages contribute to host defenses against influenza. Enhancing their function contributed to protection against influenza and other acute lethal pulmonary infections. Wild-type mice and Tg mice expressing GM-CSF in the lung were infected with influenza virus, and lung pathology, weight loss and mortality were measured. GM-CSF was also administered to lungs of wild-type mice that were infected with influenza virus. All Tg mice expressing GM-CSF in the lungs survived with greatly reduced weight loss and lung injury and histologic evidence of a rapid host inflammatory response that controlled infection vs. wild-type mice not expressing GM-CSF in the lungs. This resistance to influenza was abrogated by elimination of alveolar phagocytes, but not by depletion of T cells, B cells or neutrophils. Tg mice had far more alveolar macrophages than wild-type mice and were more resistant to influenza-induced apoptosis. Delivery of intranasal GM-CSF to wild-type mice also conferred influenza resistance. Therefore, GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages. Pulmonary delivery of GM-CSF is therefore useful for reducing the significant morbidity and mortality due to influenza virus and is similarly useful in pulmonary infection caused by other infectious viral and bacterial agents.
