Abstract
Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.
Highlights
Bronchial epithelium is directly in contact with the environment and its barrier function is essential to protect the lung from the entrance of pathogens, allergens, or irritant particulates and to maintain homeostasis (Bals and Hiemstra, 2004; Whitsett, 2015)
T-helper 2 (Th2) cells produce several cytokines such as IL5 involved in the recruitment of eosinophils which in turn produce chronically inflammatory mediators leading to the loss of epithelial integrity (Barnes, 2008), a process that will be described in more detail below
The expression of the iNOS enzyme is increased in the peripheral lung tissues of chronic obstructive pulmonary disease (COPD) patients and is associated with epithelial-cell-derived nitrosative stress, which causes oxidation and tyrosine nitration of several lung proteins generating an amplification of the inflammatory response
Summary
Bronchial epithelium is directly in contact with the environment and its barrier function is essential to protect the lung from the entrance of pathogens, allergens, or irritant particulates and to maintain homeostasis (Bals and Hiemstra, 2004; Whitsett, 2015). On the apico-lateral border of epithelial cells are present tight junctions, adherens junctions, and desmosomes forming the apical junctional complex (AJC) These proteins are connected to the cytoskeleton and fundamental to maintain the structure of the airway epithelium (Whitsett, 2015). Airway epithelial cells secrete several molecules, proteins, and peptides such as enzymes, protease inhibitors or oxidants that accumulate in the airways surface liquid and regulate inflammation, chemotaxis, antimicrobial defense, antioxidant levels, repair, and remodeling (Gohy et al, 2020) These functions are key important to avoiding the entry of pathogens and harmful particles without inducing inflammation. In the lung epithelium, there is a constitutive iNOS expression This might be because NO is essential to maintain barrier integrity, avoid the entrance of pathogens, and regulate ciliary beating, among other functions, processes that will be more detailed below (Mattila and Thomas, 2014). The use of PDE5 inhibitors is being investigated to treat other pathologies (Dupont et al, 2014) such as in CF, in which PDE5 inhibitors might correct abnormalities on transepithelial ion transport (Noel et al, 2012)
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