Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States.
Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Oct 1;325(4):L467-L476. doi: 10.1152/ajplung.00104.2023. Epub 2023 Aug 22.
The airway epithelial barrier is crucial for defending against respiratory insults and diseases. Disruption of epithelial integrity contributes to respiratory diseases, and sex-specific differences in susceptibility and severity have been observed. However, sex-specific differences in the context of respiratory diseases are often overlooked, especially in murine models. In this study, we investigated the in vitro transcriptomics of male and female murine tracheal epithelial cells (mTECs) in response to chronic cigarette smoke (CS) exposure using an International Organization for Standardization (ISO) puff regimen. Our findings reveal sex-specific differences in the baseline characteristics of airway epithelial cells. Female mTECs demonstrated stronger barrier function and higher ciliary function compared with males. The barrier function was disrupted in both males and females following chronic CS, but the difference was more significant in females due to their higher baseline. Female mice exhibited transcriptional signatures suggesting dedifferentiation with increased basal cells and markers of cellular senescence. Pathway analysis indicated potential protective roles of planar cell polarity (PCP) in preventing dedifferentiation in male mice exposed to CS. We also observed sex-specific differences in the DNA damage response and antioxidant levels, suggesting distinct mechanisms underlying cellular stress. Understanding these sex-specific mechanisms could facilitate the development of targeted therapeutic strategies for lung diseases associated with environmental insults. Recognizing sex-based differences in disease susceptibility and treatment response can lead to personalized care and improved outcomes. Clinical trials should consider sex as a biological variable to develop effective interventions that address the unique differences between men and women in respiratory diseases. The study underscores the importance of considering sex-specific differences in the airway epithelium in respiratory diseases such as COPD. Differences in gene expression between males and females at baseline and in response to chronic injury in the airway epithelium could have implications on disease susceptibility, both in COPD and other respiratory diseases. Therefore, understanding these differences is crucial for developing targeted therapies to treat respiratory diseases based on a sex-specific manner.
气道上皮屏障对于抵御呼吸道损伤和疾病至关重要。上皮完整性的破坏导致呼吸道疾病,并且观察到易感性和严重程度存在性别特异性差异。然而,在呼吸道疾病的背景下,性别特异性差异往往被忽视,尤其是在小鼠模型中。在这项研究中,我们使用国际标准化组织(ISO)的脉冲方案,研究了慢性香烟烟雾(CS)暴露下雄性和雌性小鼠气管上皮细胞(mTEC)的体外转录组学。我们的研究结果揭示了气道上皮细胞的基线特征存在性别特异性差异。与男性相比,雌性 mTEC 表现出更强的屏障功能和更高的纤毛功能。慢性 CS 后,雄性和雌性的屏障功能均受到破坏,但由于女性的基线更高,差异更为明显。雌性小鼠表现出转录特征,表明去分化增加了基底细胞和细胞衰老标志物。通路分析表明,平面细胞极性(PCP)在防止 CS 暴露的雄性小鼠去分化方面可能具有潜在的保护作用。我们还观察到 DNA 损伤反应和抗氧化剂水平存在性别特异性差异,表明细胞应激存在不同的机制。了解这些性别特异性机制可以促进针对与环境损伤相关的肺部疾病的靶向治疗策略的发展。认识到疾病易感性和治疗反应的性别差异可以实现个性化护理并改善结果。临床试验应考虑将性别作为生物学变量,以开发针对男性和女性在呼吸道疾病中独特差异的有效干预措施。该研究强调了在 COPD 等呼吸道疾病中考虑气道上皮的性别特异性差异的重要性。在基线和气道上皮慢性损伤时,男性和女性之间的基因表达差异可能对疾病易感性产生影响,无论是在 COPD 还是其他呼吸道疾病中。因此,了解这些差异对于开发基于性别特异性的治疗呼吸道疾病的靶向疗法至关重要。