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Chronic exposure to environmental pollutants is a major contributor to the development and progression of obstructive airway diseases, including asthma and COPD. Understanding the mechanisms underlying the development of obstructive lung diseases upon exposure to inhaled pollutants will lead to novel insights into the pathogenesis, prevention and treatment of these diseases. The respiratory epithelial lining forms a robust physicochemical barrier protecting the body from inhaled toxic particles and pathogens. Inhalation of airborne particles and gases may impair airway epithelial barrier function and subsequently lead to exaggerated inflammatory responses and airway remodelling, which are key features of asthma and COPD. In addition, air pollutant-induced airway epithelial barrier dysfunction may increase susceptibility to respiratory infections, thereby increasing the risk of exacerbations and thus triggering further inflammation. In this review, we discuss the molecular and immunological mechanisms involved in physical barrier disruption induced by major airborne pollutants and outline their implications in the pathogenesis of asthma and COPD. We further discuss the link between these pollutants and changes in the lung microbiome as a potential factor for aggravating airway diseases. Understanding these mechanisms may lead to identification of novel targets for therapeutic intervention to restore airway epithelial integrity in asthma and COPD., Competing Interests: Conflict of interest: M. Aghapour reports personal fees from Kommission zur Förderung des wissenschaftlichen Nachwuchses, Medical Faculty, Otto-von-Guericke University, Magdeburg, non-financial support from German Research Foundation, funded by grant 361210922/RTG 2408, outside the submitted work. Conflict of interest: N.D. Ubags has nothing to disclose. Conflict of interest: D. Bruder reports grants from German Research Foundation, grant number 361210922/RTG 2408, outside the submitted work. Conflict of interest: P.S. Hiemstra reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: V. Sidhaye has nothing to disclose. Conflict of interest: F. Rezaee has nothing to disclose. Conflict of interest: I.H. Heijink has nothing to disclose., (Copyright ©The authors 2022.)

Pharmacologic agonism of the β 2 -adrenergic receptor (β 2 AR) induces bronchodilation by activating the enzyme adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). β 2 AR agonists are generally the most effective strategy to relieve acute airway obstruction in asthmatic patients, but they are much less effective when airway obstruction in young patients is triggered by infection with respiratory syncytial virus (RSV). Here, we investigated the effects of RSV infection on the abundance and function of β 2 AR in primary human airway smooth muscle cells (HASMCs) derived from pediatric lung tissue. We showed that RSV infection of HASMCs resulted in proteolytic cleavage of β 2 AR mediated by the proteasome. RSV infection also resulted in β 2 AR ligand-independent activation of adenylyl cyclase, leading to reduced cAMP synthesis compared to that in uninfected control cells. Last, RSV infection caused stronger airway smooth muscle cell contraction in vitro due to increased cytosolic Ca 2+ concentrations. Thus, our results suggest that RSV infection simultaneously induces loss of functional β 2 ARs and activation of multiple pathways favoring airway obstruction in young patients, with the net effect of counteracting β 2 AR agonist-induced bronchodilation. These findings not only provide a potential mechanism for the reported lack of clinical efficacy of β 2 AR agonists for treating virus-induced wheezing but also open the path to developing more precise therapeutic strategies., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The transient receptor potential vanilloid 1 (TRPV 1 ) channel is expressed in human bronchial epithelium (HBE), where it transduces Ca 2+ in response to airborne irritants. TRPV 1 activation results in bronchoconstriction, cough, and mucus production, and may therefore contribute to the pathophysiology of obstructive airway disease. Since children with asthma face the greatest risk of developing virus-induced airway obstruction, we hypothesized that changes in TRPV 1 expression, localization, and function in the airway epithelium may play a role in bronchiolitis and asthma in childhood. We sought to measure TRPV 1 protein expression, localization, and function in HBE cells from children with versus without asthma, both at baseline and after RSV infection. We determined changes in TRPV 1 protein expression, subcellular localization, and function both at baseline and after RSV infection in primary HBE cells from normal children and children with asthma. Basal TRPV 1 protein expression was higher in HBE from children with versus without asthma and primarily localized to plasma membranes (PMs). During RSV infection, TRPV 1 protein increased more in the PM of asthmatic HBE as compared with nonasthmatic cells. TRPV 1 -mediated increase in intracellular Ca 2+ was greater in RSV-infected asthmatic cells, but this increase was attenuated when extracellular Ca 2+ was removed. Nerve growth factor (NGF) recapitulated the effect of RSV on TRPV 1 activation in HBE cells. Our data suggest that children with asthma have intrinsically hyperreactive airways due in part to higher TRPV 1 -mediated Ca 2+ influx across epithelial membranes, and this abnormality is further exacerbated by NGF overexpression during RSV infection driving additional Ca 2+ from intracellular stores.

Airway epithelial cells form a barrier to the outside world and are at the front line of mucosal immunity. Epithelial apical junctional complexes are multiprotein subunits that promote cell-cell adhesion and barrier integrity. Recent studies in the skin and gastrointestinal tract suggest that disruption of cell-cell junctions is required to initiate epithelial immune responses, but how this applies to mucosal immunity in the lung is not clear. Increasing evidence indicates that defective epithelial barrier function is a feature of airway inflammation in asthmatic patients. One challenge in this area is that barrier function and junctional integrity are difficult to study in the intact lung, but innovative approaches should provide new knowledge in this area in the near future. In this article we review the structure and function of epithelial apical junctional complexes, emphasizing how regulation of the epithelial barrier affects innate and adaptive immunity. We discuss why defective epithelial barrier function might be linked to TH2 polarization in asthmatic patients and propose a rheostat model of barrier dysfunction that implicates the size of inhaled allergen particles as an important factor influencing adaptive immunity., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Recent published studies have highlighted the complexity of the immune response to allergens, and the various asthma phenotypes that arise as a result. Although the interplay of regulatory and effector immune cells responding to allergen would seem to dictate the nature of the asthmatic response, little is known regarding how tolerance versus reactivity to allergen occurs in the lung. The vast majority of mouse models study allergen encounter in naive animals, and therefore exclude the possibility that previous encounters with allergen may influence future sensitization. To address this, we studied sensitization to the model allergen OVA in mice in the context of pre-existing tolerance to OVA. Allergen sensitization by either systemic administration of OVA with aluminum hydroxide or mucosal administration of OVA with low-dose LPS was suppressed in tolerized animals. However, higher doses of LPS induced a mixed Th2 and Th17 response to OVA in both naive and tolerized mice. Of interest, tolerized mice had more pronounced Th17-type inflammation than did naive mice receiving the same sensitization, suggesting pre-existing tolerance altered the inflammatory phenotype. These data show that a pre-existing tolerogenic immune response to allergen can affect subsequent sensitization in the lung. These findings have potential significance for understanding late-onset disease in individuals with severe asthma.

Negative regulation of innate immune responses is essential to prevent excess inflammation and tissue injury and promote homeostasis. Lysophosphatidic acid (LPA) is a pleiotropic lipid that regulates cell growth, migration, and activation and is constitutively produced at low levels in tissues and in serum. Extracellular LPA binds to specific G protein-coupled receptors, whose function in regulating innate or adaptive immune responses remains poorly understood. Of the classical LPA receptors belonging to the Edg family, lpa2 (edg4) is expressed by dendritic cells (DC) and other innate immune cells. In this article, we show that DC from lpa2(-/-) mice are hyperactive compared with their wild-type counterparts and are less susceptible to inhibition by different LPA species. In transient-transfection assays, we found that lpa2 overexpression inhibits NF-κB-driven gene transcription. Using an adoptive-transfer approach, we found that allergen-pulsed lpa2(-/-) DC induced substantially more lung inflammation than did wild-type DC after inhaled allergen challenge. Finally, lpa2(-/-) mice develop greater allergen-driven lung inflammation than do their wild-type counterparts in models of allergic asthma involving both systemic and mucosal sensitization. Taken together, these findings identify LPA acting via lpa2 as a novel negative regulatory pathway that inhibits DC activation and allergic airway inflammation.

Immune responses can be compartmentalized into innate versus adaptive components. This relatively recent dichotomy positioned the innate immune system at the interface between the host and the external environment and provided a new conceptual framework with which to view allergic diseases, including asthma. Airway epithelial cells and dendritic cells are key components of the innate immune system in the nose and lung and are now known to be intimately involved in allergen recognition and in modulating allergic immune responses. Here we review current thinking about how these two key cell types sense and respond to inhaled allergens, and emphasize how an understanding of "allergic innate immunity" can translate into new thinking about mechanisms of allergen sensitization and potentially lead to new therapeutic targets.