Lung microvascular occlusion by platelet-rich neutrophil-platelet aggregates promotes cigarette smoke–induced severe flu
Tomasz W. Kaminski, Tomasz Brzoska, Xiuying Li, Ravi Vats, Omika Katoch, Rikesh K. Dubey, Kamal Bagale, Simon C. Watkins, Bryan J. McVerry, Tirthadipa Pradhan-Sundd, Lianghui Zhang, Keven M. Robinson, Toru Nyunoya, Prithu Sundd
Tomasz W. Kaminski, Tomasz Brzoska, Xiuying Li, Ravi Vats, Omika Katoch, Rikesh K. Dubey, Kamal Bagale, Simon C. Watkins, Bryan J. McVerry, Tirthadipa Pradhan-Sundd, Lianghui Zhang, Keven M. Robinson, Toru Nyunoya, Prithu Sundd
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Research Article Infectious disease Pulmonology

Lung microvascular occlusion by platelet-rich neutrophil-platelet aggregates promotes cigarette smoke–induced severe flu

Abstract

Cigarette smoking is associated with a higher risk of ICU admissions among patients with flu. However, the etiological mechanism by which cigarette smoke (CS) exacerbates flu remains poorly understood. Here, we show that a mild dose of influenza A virus promotes a severe lung injury in mice preexposed to CS but not room air for 4 weeks. Real-time intravital (in vivo) lung imaging revealed that the development of acute severe respiratory dysfunction in CS- and flu-exposed mice was associated with the accumulation of platelet-rich neutrophil-platelet aggregates (NPAs) in the lung microcirculation within 2 days following flu infection. These platelet-rich NPAs formed in situ and grew larger over time to occlude the lung microvasculature, leading to the development of pulmonary ischemia followed by the infiltration of NPAs and vascular leakage into the alveolar air space. These findings suggest, for the first time to our knowledge, that an acute onset of platelet-driven thrombo-inflammatory response in the lung contributes to the development of CS-induced severe flu.

Authors

Tomasz W. Kaminski, Tomasz Brzoska, Xiuying Li, Ravi Vats, Omika Katoch, Rikesh K. Dubey, Kamal Bagale, Simon C. Watkins, Bryan J. McVerry, Tirthadipa Pradhan-Sundd, Lianghui Zhang, Keven M. Robinson, Toru Nyunoya, Prithu Sundd

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Figure 5

Pulmonary ischemia leads to severe vascular leakage in the lung of CS+Flu mice.

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Pulmonary ischemia leads to severe vascular leakage in the lung of CS+Fl...
Mice exposed to CS or RA for 4 weeks followed by inoculation with Flu, and qFILM used to assess thrombo-inflammation in the lung at 4 days after infection. Microcirculation (pseudocolored purple), neutrophils (red), and platelets (pseudocolored green). qFILM images of the lung microcirculation in an (A) RA+Flu and (B) CS+Flu mouse showing alveolar air spaces with (#) or without (*) vascular leakage (presence of purple vascular dye in air spaces). Right panels show magnified view of the dashed box in left panels. Dashed contours in right panels mark the walls of the pulmonary microvessels bordering the alveolar air spaces. Presence (A; right panel) and absence (B; right panel) of vascular dye between the dashed contours suggests the presence or absence of blood flow in microvessels. Refer to Supplemental Videos 13 and 14. Scale bars: 50 µm (left panels) and 20 µm (right panels). qFILM images were analyzed to compare (C) percent field of views (FOVs) with vascular leakage and (D) size of vascular leakage areas in the lung of RA+Flu and CS+Flu mice. Data in C are shown as percentages and compared using χ2 distribution test. Data in D are shown as mean ± SEM and compared using Students’ t test. n = 5 mice/group and ~6–8 FOVs per mouse. *P < 0.05. FOV size, ~65,000 µm2. (E) Cropped qFILM image of the same FOV in the lung of a CS+Flu mouse show 2 neutrophils crawling intravascularly in opposite directions (shown by arrows). One neutrophil crawls to the left; meanwhile, the second neutrophil crawls to the right and transmigrates into the air space. Arrowhead marks the disappearing tail of the emigrating neutrophil. Refer to Supplemental Video 15. Scale bar: 10 µm.