Large Scale Single Cell RNA sequencing Analysis of Lung Tissue and Bronchoalveolar Lavage Fluid from Patients with Chronic Obstructive Pulmonary Disease, COVID-19 and Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology, primarily characterized by the development of fibrosis. IPF affects 3–9 out of every 100,000 people globally, with its prevalence on the rise. Early perspectives posited that IPF was a chronic inflammatory disease. However, due to the lack of evidence supporting sustained inflammation in IPF and the limited efficacy of corticosteroid treatments, this theory has been increasingly discredited.The few pharmacotherapies available have demonstrated limited effectiveness, and lung transplantation remains the only definitive treatment option for IPF. <br/> Recent evidence increasingly indicates that IPF is associated with the loss or apoptosis of alveolar type 2 cells (AT2), which subsequently leads to dysregulated repair mechanisms and the pathogenic activation of fibroblasts. This observation evokes parallels with another disease characterized by AT2 cell damage: the recent global pandemic of COVID-19, which severe cases are also associated with the development of pulmonary fibrosis during the acute respiratory distress syndrome phase. Consequently, it is imperative to elucidate the central molecular mechanisms involving AT2 cells in these diseases. <br/> Alveolar macrophages represent a specialized population of immune cells localized within the alveolar spaces, serving as sentinel guardians that play a critical role in maintaining pulmonary homeostasis and providing defense against pathogens. Therefore, elucidating the key regulatory hub that influence the functional outcomes of Alveolar macrophages is essential for optimizing their therapeutic potential in lung diseases. <br/> In this study, we integrated 22 single-cell sequencing datasets pertaining to COPD, IPF, and COVID-19, and conducted a comprehensive analysis focusing on five major aspects: cell proportions, differentially expressed genes, cytokine profiles, the correlations with clinical indicators, and cellular interactions.Our findings revealed an increase in monocyte populations within the lung tissue of COPD patients, contrasting with a decrease observed in both COVID19 and IPF patients. Additionally, proliferative macrophages were found to be elevated in the lung tissue of IPF patients, while their presence was diminished in cases of COVID-19 and COPD. In respect of chemokine expression, Monocytes were found to express high level of CXCL8 in patients with COVID-19. In relation to clinical indicators, our study identified that gender differences across all three diseases led to alterations in alveolar epithelial cells. Furthermore, we also observed a positive correlation between macrophage subtypes and age in patients with COVID-19. With respect to the cellular communication, our findings indicate that in IPF, Apoptosis AT2 engage in cellular communication with macrophages subtypes (via the MK signaling pathway. Thus, our study reveals disease-specific profiles in alveolar epithelial cells and macrophages among COPD, IPF and COVID-19, highlighting potential therapeutic targets across these diseases.