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
View: Text | PDF
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

×

Figure 1

CS+Flu promotes severe lung injury in mice.

Options: View larger image (or click on image) Download as PowerPoint
CS+Flu promotes severe lung injury in mice. (A) Experimental scheme. WT ...
(A) Experimental scheme. WT mice exposed to cigarette smoke (CS) or room air (RA) for 4 weeks followed by intranasal inoculation with influenza A virus (flu) or sterile PBS as vehicle (Veh). Body weight was measured every day after inoculation for 14 days, and lung injury was assessed at day 9 after inoculation. (B and C) Percent drop in body weight and absolute body weight at day 0, 9, and 14 after inoculation in RA+Flu and CS+Flu mice (n = 16 per group). (D) Representative H&E-stained histological sections of the whole left lung of an RA+Veh, RA+Flu, and CS+Flu mouse at day 9 after inoculation. Scale bars: 100 μm. (E–J) Lung histological sections were scored (refer to Methods for details, n = 8–16 per group) for severity of hemorrhage (E), pulmonary edema (F), vascular congestion (G), alveolar wall thickening (H), percentage of injured area (I), and percent blood oxygen saturation in RA+Veh, RA+Flu and CS+Flu mice (J) (n = 3–12 per group) at day 4 after inoculation. (K) Relative mRNA expression of Influenza M1 Protein (refer Methods for details) at different days after flu infection in RA+Flu and CS+Flu mice (n = 3–5 per group). Data are shown as mean ± SEM and compared using Student’s t test. Comparative statistical analysis was performed by 1-way ANOVA. Comparative statistical analysis was performed by 1-way ANOVA with Bonferroni correction. *P < 0.05; **P < 0.01; ***P < 0.001.