Background: Influenza is an acute respiratory disease primarily caused by the influenza-A virus (IAV), which affects over~35million people in the US annually. Epidemiological evidence suggests that prior exposure to cigarette smoke (CS) or habitual smoking increases the risk of  IAV-triggered respiratory failure (severe flu). Although emerging evidence supports the role of thrombo-inflammation in the development of CS and IAV-triggered lung injury, the innate immune mechanism contributing to this morbidity remains poorly understood.

Aims: Our aim was to investigate the platelets-neutrophil interplay in lung microcirculation during CS-induced severe flu in mice.

Methods: 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 intranasal administration of A/PR/8/34 (H1N1) IAV. The body weight was measured every day for two weeks after IAV administration followed by assessment of lung injury at days-7 and-14. Lungs were harvested for histological assessment of injury and estimation of viral titer by qPCR. Quantitative fluorescence intravital lung microscopy (qFILM) was conducted 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.  

Results: Mice exposed to CS+IAV manifested significantly more weight loss, lung injury, lung congestion, alveolar 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.

Conclusions: 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 in neutrophils and platelets that drive this hyper thrombo-inflammatory response.  

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/platelet-rich-neutrophil-platelet-micro-emboli-contribute-to-cigarette-smoke-induced-influenza-severity/