Abstract
Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.
Highlights
The pulmonary epithelium is a complex, tightly regulated system required for effective respiratory function, which differs considerably depending on its location within the respiratory tract and displays diverse physiological roles
Stimulation of pattern recognition receptors (PRRs) via pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs) is a critical component of the innate immune response to damage, causing activation of numerous proinflammatory pathways involved in the immune response to pathogens as well as contributing to disease pathogenesis of non-infectious lung diseases
There is a growing body of evidence which suggests that the cytokine storm seen in severe coronavirus disease (COVID)-19 cases is consistent with dysregulated cell death signalling pathways and a hyper inflammatory immune response mediated by increased DAMP signalling in the lung
Summary
The pulmonary epithelium is a complex, tightly regulated system required for effective respiratory function, which differs considerably depending on its location within the respiratory tract and displays diverse physiological roles. Epithelial cells are situated at the interface between the internal and external environment and exert many important functions to maintain tissue integrity, including mucociliary clearance, maintenance of tight junctions and epithelial adherence and secretion of antibacterial, antimicrobial and antiprotease molecules [6,7,8,9,10,11]. Due to their location, pulmonary epithelial cells are uniquely susceptible to injury and face substantial challenges to tissue integrity such as routine exposure to a range of exogenous stressors including, but not limited to, bacterial and viral insult, cigarette smoke, asbestos and airborne pollutants [12]. We will review how epithelial cells drive inflammation and fibrosis through interactions with immune cells and fibroblasts and explore emerging concepts around the role of epithelial damage and cell death cascades in pulmonary disease
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