Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
Advanced Research Facilities and Services, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Shizuoka, Japan.
Am J Physiol Lung Cell Mol Physiol. 2024 Sep 1;327(3):L406-L414. doi: 10.1152/ajplung.00114.2024. Epub 2024 Aug 6.
Obesity is a risk factor for increased morbidity and mortality in viral respiratory infection. Mucociliary clearance (MCC) in the airway is the primary host defense against viral infections. However, the impact of obesity on MCC is unclear, prompting this study. Using murine tracheal tissue culture and in vitro influenza A virus (IAV) infection models, we analyzed cilia-driven flow and ciliary beat frequency (CBF) in the airway epithelium to evaluate MCC. Short-term IAV infection increased cilia-driven flow and CBF in control mice, but not in high-fat diet-induced obese mice. Basal cilia-driven flow and CBF were also lower in obese mice than in control mice. Mechanistically, the increase of extracellular adenosine triphosphate (ATP) release during IAV infection, which was observed in the control mice, was abolished in the obese mice; however, the addition of ATP increased cilia-driven flow and CBF both in control and obese mice to a similar extent. In addition, RNA sequencing and reverse transcription-polymerase chain reaction revealed the downregulation of several cilia-related genes, including , , and (the dynein-related genes); (the polychaete differentiation gene); (the ciliogenesis and intraflagellar transport gene); , , and (the radial spoke structure and assembly gene); and (the nexin-dynein regulatory complex genes) in obese murine tracheal tissues compared with their control levels. In conclusion, our studies demonstrate that obesity attenuates MCC under basal conditions and during IAV infection by downregulating the expression of cilia-related genes and suppressing the release of extracellular ATP, thereby increasing the susceptibility and severity of IAV infection. Our study shows that obesity impairs airway mucociliary clearance (MCC), an essential physical innate defense mechanism for viral infection. Mechanically, this is likely due to the obesity-induced downregulation of cilia-related genes and attenuation of extracellular ATP release. This study provides novel insights into the mechanisms driving the higher susceptibility and severity of viral respiratory infections in individuals with obesity.
肥胖是病毒呼吸道感染发病率和死亡率增加的一个危险因素。气道中的黏液纤毛清除（MCC）是抵抗病毒感染的主要宿主防御机制。然而，肥胖对 MCC 的影响尚不清楚，促使我们进行了这项研究。我们使用鼠气管组织培养和体外流感 A 病毒（IAV）感染模型，分析气道上皮细胞中纤毛驱动的流动和纤毛拍打频率（CBF），以评估 MCC。短期 IAV 感染增加了对照组小鼠的纤毛驱动流动和 CBF，但在高脂肪饮食诱导的肥胖小鼠中则没有。肥胖小鼠的基础纤毛驱动流动和 CBF 也低于对照组小鼠。在机制上，我们观察到对照组小鼠在 IAV 感染期间细胞外三磷酸腺苷（ATP）释放增加，但肥胖小鼠则没有；然而，在对照组和肥胖小鼠中，ATP 的添加均使纤毛驱动的流动和 CBF 增加到相似的程度。此外，RNA 测序和逆转录-聚合酶链反应显示，与对照组相比，肥胖小鼠气管组织中的几个纤毛相关基因的表达下调，包括 （动蛋白相关基因）； （多毛分化基因）； （纤毛发生和鞭毛内运输基因）； （辐射状 spoke 结构和组装基因）；和 （nexin-dynein 调节复合物基因）。总之，我们的研究表明，肥胖通过下调纤毛相关基因的表达和抑制细胞外 ATP 的释放，在基础条件下和 IAV 感染期间削弱了 MCC，从而增加了 IAV 感染的易感性和严重程度。我们的研究表明，肥胖会损害气道黏液纤毛清除（MCC），这是一种抵抗病毒感染的基本物理先天防御机制。从机制上讲，这可能是由于肥胖诱导的纤毛相关基因下调和细胞外 ATP 释放减弱所致。这项研究为肥胖个体中病毒呼吸道感染更高的易感性和严重程度提供了新的见解。
