Platelet-rich neutrophil-platelet micro-emboli contribute to cigarette smoke induced flu severity.

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Abstract Epidemiological evidence suggests that prior exposure to cigarette smoke (CS) or habitual smoking increases the risk of influenza A virus (IAV)-triggered respiratory failure. Although emerging evidence supports the role of thrombo-inflammation in the development of CS and IAV-triggered lung injury, the innate immune mechanism remains poorly understood. We have developed a two-hit model of CS-induced severe flu in mice. Mice were exposed to four weeks of room air (air) or CS followed by intra-nasal administration of A/PR/8/34 IAV. The body weight was measured every day for two weeks after IAV administration followed by assessment of lung injury at day 7. Lungs were harvested for histological assessment and viral titration by qPCR. Quantitative fluorescence intravital lung microscopy (qFILM) was conducted at 2-, 3- and 4-days post IAV-infection to visualize dynamics of neutrophil and platelet recruitment in the lung of mice IV administered with fluorescent dextran, anti-Ly6G Ab and anti-CD49Abs. Mice exposed to CS+IAV manifested significantly more weight loss, lung injury, lung congestion, hemorrhage and hypoxemia compared to mice administered IAV only. QFILM revealed that severity of lung injury was associated with significantly larger area with impaired blood flow and more vascular leakage secondary to vascular occlusion by platelet-rich neutrophil-platelet aggregates in the lung of CS+IAV than IAV administered mice. These initial results suggest that CS primes innate immune signaling in neutrophils and platelets to promote their recruitment in the lung following flu, leading to severe acute lung injury. Currently, studies are underway to identify innate immune pathways that drive hyper thrombo-inflammatory response.