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The severity of coronavirus disease 2019 (COVID-19) is linked to an increasing number of risk factors, including exogenous (environmental) stimuli such as air pollution, nicotine, and cigarette smoke. These three factors increase the expression of angiotensin I converting enzyme 2 (ACE2), a key receptor involved in the entry of severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2)--the etiological agent of COVID-19--into respiratory tract epithelial cells. Patients with severe COVID-19 are managed with oxygen support, as are at-risk individuals with chronic lung disease. To date, no study has examined whether an increased fraction of inspired oxygen (FiO2) may affect the expression of SARS-CoV-2 entry receptors and co-receptors, including ACE2 and the transmembrane serine proteases TMPRSS1, TMPRSS2, and TMPRSS11D. To address this, steady-state mRNA levels for genes encoding these SARS-CoV-2 receptors were assessed in the lungs of mouse pups chronically exposed to elevated FiO2, and in the lungs of preterm-born human infants chronically managed with an elevated FiO2. These two scenarios served as models of chronic elevated FiO2 exposure. Additionally, SARS-CoV-2 receptor expression was assessed in primary human nasal, tracheal, esophageal, bronchial, and alveolar epithelial cells, as well as primary mouse alveolar type II cells exposed to elevated oxygen concentrations. While gene expression of ACE2 was unaffected, gene and protein expression of TMPRSS11D was consistently upregulated by exposure to an elevated FiO2. These data highlight the need for further studies that examine the relative contribution of the various viral co-receptors on the infection cycle, and point to oxygen supplementation as a potential risk factor for COVID-19. [ABSTRACT FROM AUTHOR]

Alveolarization is the process by which the alveoli, the principal gas exchange units of the lung, are formed. Along with the maturation of the pulmonary vasculature, alveolarization is the objective of late lung development. The terminal airspaces that were formed during early lung development are divided by the process of secondary septation, progressively generating an increasing number of alveoli that are of smaller size, which substantially increases the surface area over which gas exchange can take place. Disturbances to alveolarization occur in bronchopulmonary dysplasia (BPD), which can be complicated by perturbations to the pulmonary vasculature that are associated with the development of pulmonary hypertension. Disturbances to lung development may also occur in persistent pulmonary hypertension of the newborn in term newborn infants, as well as in patients with congenital diaphragmatic hernia. These disturbances can lead to the formation of lungs with fewer and larger alveoli and a dysmorphic pulmonary vasculature. Consequently, affected lungs exhibit a reduced capacity for gas exchange, with important implications for morbidity and mortality in the immediate postnatal period and respiratory health consequences that may persist into adulthood. It is the objective of this Perspectives article to update the reader about recent developments in our understanding of the molecular mechanisms of alveolarization and the pathogenesis of BPD. [ABSTRACT FROM AUTHOR]

The gasotransmitter hydrogen sulfide (H2S) is emerging as a mediator of lung physiology and disease. Recent studies revealed that H2S administration limited perturbations to lung structure in experimental animal models of bronchopulmonary dysplasia (BPD), partially restoring alveolarization, limiting pulmonary hypertension, limiting inflammation, and promoting epithelial repair. No studies have addressed roles for endogenous H2S in lung development. H2S is endogenously generated by cystathionine β-synthase (Cbs) and cystathionine γ-lyase (Cth). We demonstrate here that the expression of Cbs and Cth in mouse lungs is dynamically regulated during lung alveolarization and that alveolarization is blunted in Cbs-/- and Cth-/- mouse pups, where a 50% reduction in the total number of alveoli was observed, without any impact on septal thickness. Laser-capture microdissection and immunofluorescence staining indicated that Cbs and Cth were expressed in the airway epithelium and lung vessels. Loss of Cbs and Cth led to a 100-500% increase in the muscularization of small- and medium-sized lung vessels, which was accompanied by increased vessel wall thickness, and an apparent decrease in lung vascular supply. Ablation of Cbs expression using small interfering RNA or pharmacological inhibition of Cth using propargylglycine in lung endothelial cells limited angiogenic capacity, causing a 30-40% decrease in tube length and a 50% decrease in number of tubes formed. In contrast, exogenous administration of H2S with GYY4137 promoted endothelial tube formation. These data confirm a key role for the H2S-generating enzymes Cbs and Cth in pulmonary vascular development and homeostasis and in lung alveolarization. [ABSTRACT FROM AUTHOR]