Tight Junctions, the Epithelial Barrier, and Toll-like Receptor-4 During Lung Injury

Abstract

Lung epithelium is constantly exposed to the environment and is critically important for the orchestration of initial responses to infectious organisms, toxins, and allergic stimuli, and maintenance of normal gaseous exchange and pulmonary function. The integrity of lung epithelium, fluid balance, and transport of molecules is dictated by the tight junctions (TJs). The TJs are formed between adjacent cells. We have focused on the topic of the TJ structure and function in lung epithelial cells. This review includes a summary of the last twenty years of literature reports published on the disrupted TJs and epithelial barrier in various lung conditions and expression and regulation of specific TJ proteins against pathogenic stimuli. We discuss the molecular signaling and crosstalk among signaling pathways that control the TJ structure and function. The Toll-like receptor-4 (TLR4) recognizes the pathogen-and damage-associated molecular patterns released during lung injury and inflammation and coordinates cellular responses. The molecular aspects of TLR4 signaling in the context of TJs or the epithelial barrier are not fully known. We describe the current knowledge and possible networking of the TLR4-signaling with cellular and molecular mechanisms of TJs, lung epithelial barrier function, and resistance to treatment strategies.

Serine protease Rv2569c facilitates transmission of Mycobacterium tuberculosis via disrupting the epithelial barrier by cleaving E-cadherin

“…The alveolar epithelial barrier serves as a critical obstacle for microbial invaders [ 31 , 32 ]. Both TJs and AJs are essential for maintaining the integrity of the epithelial barrier, establishing epithelial polarity, and promoting cell–cell contact [ 18 ]. The disruption of the epithelial barrier, either directly or indirectly, is a crucial factor in the ability of many respiratory bacterial pathogens to cause severe systemic infections [ 33 – 35 ].…”

“…epithelial polarity, and promoting cell-cell contact [18]. The disruption of the epithelial barrier, either directly or indirectly, is a crucial factor in the ability of respiratory bacterial pathogens to cause severe systemic infections [33][34][35].…”

“…The alveolar epithelial barrier is essential in defending against invading pathogens and toxins by performing a biological barrier function through the presence of mucociliary clearance and intercellular junctions [16,17]. Tight junctions (TJs) and adherens junctions (AJs) are intercellular junctions that contribute to the formation and maintenance of this barrier [18,19]. TJs consist of several protein elements, such as tricellulin, occludin, claudin, and junctional adhesion molecule, which are transmembrane proteins linked to the actin cytoskeleton between neighboring cells [20][21][22].…”

β-Sitosterol Enhances Lung Epithelial Cell Permeability by Suppressing the NF-κB Signaling Pathway

“…The group of transmembrane proteins within tight junctions encompasses diverse components such as tight junction-associated Marvel proteins, claudins, and members of the immunoglobulin superfamily. In contrast, peripheral membrane proteins linked to tight junctions include F-actin, scaffold proteins that interact with F-actin or do not bind to F-actin, molecules responsible for cell polarity, and factors in cell signaling pathways [21]. Claudin-4 and claudin-5 are examples of claudins, which are critical in maintaining the alveolar epithelial cell barrier function [12,22].…”

Asthma: a New Approach to the Bronchial Epithelium

“…Targeting the airway epithelial barrier presents a viable and innovative therapeutic strategy for asthma and related allergic diseases, given the pivotal role intrinsic abnormalities in the airway epithelium play in fostering inappropriate immune responses and defective repair mechanisms. The exploration of genetically supported targets and pathways that contribute to maintaining or enhancing epithelial barrier function, including those improving mucosal innate immunity, enhancing tight junction and adherens junction protein assembly, and promoting epithelial cell integrity -offers substantial potential (28)(29)(30). Recent advancements, such as the inhibition of β-catenin/CBP signaling to prevent epithelial-mesenchymal transition and enhance barrier recovery, along with the modulation of Notch signaling impacting mucus secretion, underline the efficacy of targeting molecular pathways to correct epithelial dysfunctions (31).…”