Pathophysiology of bronchoconstriction

Abstract

Purpose of review To provide an overview on the present understanding of roles of oxidative DNA damage repair in cell signaling underlying bronchoconstriction common to, but not restricted to various forms of asthma and chronic obstructive pulmonary disease Recent findings Bronchoconstriction is a tightening of smooth muscle surrounding the bronchi and bronchioles with consequent wheezing and shortness of breath. Key stimuli include air pollutants, viral infections, allergens, thermal and osmotic changes, and shear stress of mucosal epithelium, triggering a wide range of cellular, vascular and neural events. Although activation of nerve fibers, the role of G-proteins, protein kinases and Ca++, and molecular interaction within contracting filaments of muscle are well defined, the overarching mechanisms by which a wide range of stimuli initiate these events are not fully understood. Many, if not all, stimuli increase levels of reactive oxygen species (ROS), which are signaling and oxidatively modifying macromolecules, including DNA. The primary ROS target in DNA is guanine, and 8-oxoguanine is one of the most abundant base lesions. It is repaired by 8-oxoguanine DNA glycosylase1 (OGG1) during base excision repair processes. The product, free 8-oxoG base, is bound by OGG1 with high affinity, and the complex then functions as an activator of small GTPases, triggering pathways for inducing gene expression and contraction of intracellular filaments in mast and smooth muscle cells. Summary Oxidative DNA damage repair-mediated cell activation signaling result in gene expression that “primes” the mucosal epithelium and submucosal tissues to generate mediators of airway smooth muscle contractions.

miR-155 Modulates Cockroach Allergen– and Oxidative Stress–Induced Cyclooxygenase-2 in Asthma

“…ROS have been shown to be crucial in pollen (16) and HDM (60)-induced allergic sensitization and asthma. In particular, ROS induced by HDM cause oxidative DNA damage and asthma-associated pathophysiology (14, 60). Recent studies have suggested that ROS in epithelial cells are a critical mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens(20) (61).…”

“…In response to environmental pollutants (e.g., ultrafine particles, diesel exhaust particles (DEP), and smoking), epithelial and mucosal inflammatory cells may produce ROS, contributing to the pathophysiology of allergic inflammation and asthma (9–12). Though studies are limited, several allergens have been shown to induce ROS production, such as cat dander (13), pollen (14–16), and house dust mite (HDM) (17, 18), leading to allergic inflammation. Airway epithelial cells are the first line of defense against inhaled allergens, and epithelial cell activation is one of the hallmark characteristics of asthma (19).…”

OGG1-DNA interactions facilitate NF-κB binding to DNA targets

“…Many reported that ROS are the central effectors in a variety of physiological processes 38 39 40 41 . Much attention have been caught by the role of ROS in posttranslational modifications of TFs (e.g., NF-κB, AP1) 34 42 43 , however, one background is neglected during transcriptional regulation, that is the simultaneous oxidative damage to cellular macromolecules, especially DNA base lesions that occur through oxidative reactions.…”

8-Oxoguanine DNA glycosylase1–driven DNA repair—A paradoxical role in lung aging

“…We have chosen lungs as it forms a barrier between environment and vertebrate organisms and its decreased function impacts entire health e.g., correlates with poorer cardiovascular performance, cognitive activities and increased subcortical atrophy, and dementia in humans (Carvalhaes-Neto et al, 1995; Janssens, 2005). In addition, environmental pollutants, osmotic, mechanical stress, and oxidative burst by immune cells in airways leads to 8-oxoG formation, consequently OGG1-BER rev in (Ba et al, 2014; Ba et al, 2015; Bacsi et al, 2016; Radak and Boldogh, 2010). Challenge of lungs with 8-oxoG base robustly increases in GTP-bound levels of KRAS but not activation of HRAS or NRAS in line with previous observations (Aguilera-Aguirre et al, 2014).…”

“…Estimates on the absolute numbers of genomic 8-oxoG lesions in airways (nasal, bonchial, bronchiolar epithelium, or subepihelial lung tissues) which directly interact with the environment is not available; however, the levels of the OGG1-BER repair products (e.g., 8-oxoG base) in serum or urine correlates well with dose and length of exposure, chemical composition, and physical nature of the inhaled environmental agents (Ba et al, 2014; Ba et al, 2015). Moreover, an increase free 8-oxoG levels in sputum and bronchoalveolar lavage fluid after environmental exposures (Ba et al, 2014; Bacsi et al, 2016; Proklou et al, 2013). In experimental animal models of lung diseases or in age-associated human lung pathologies (e.g., COPD, emphysema, and asthma) showed that one of the most referenced DNA base damage(s) is 8-oxoG (Ba et al, 2014; Ba et al, 2015; Deslee et al, 2009; Igishi et al, 2003).…”