Contribution of alveolar type II cell‐derived cyclooxygenase‐2 to basal airway function, lung inflammation, and lung fibrosis

Abstract

Cyclooxygenase (COX)-2 has been shown to be involved in regulating basal airway function, bacterial LPS-induced airway hyperresponsiveness (AHR) and lung inflammation, and bleomycin-induced lung fibrosis; however, the cellular source of COX-2 that underlies these effects is unknown. We generated mice with alveolar type II (ATII) cell-specific knockdown of COX-2 (AT2CC 2/2 ), to examine the role of ATII cellderived prostaglandins (PGs) in these processes. Specific knockdown of COX-2 was confirmed by real-time RT-PCR and Western blot analyses. LC/MS/MS analysis showed that ATII cells produced PGs. Basal airway responsiveness of AT2CC 2/2 mice was decreased compared to that of wild-type (WT) mice. LPS-induced hypothermic response, infiltration of inflammatory cells into the airway, and lung inflammation were enhanced in AT2CC 2/2 mice relative to WT controls; however, LPSinduced AHR and proinflammatory cytokine and chemokine expression were similar between the genotypes. After 21 d of bleomycin administration, AT2CC 2/2 mice behaved in a manner similar to WT mice. Thus, ATII cell-derived COX-2 plays an important role in regulating basal airway function and LPS-induced lung inflammation, but does not play a role in bleomycininduced fibrosis. These findings provide insight into the cellular source of COX-2 related to these lung

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

“…Findings that it remained elevated for at least 21 d are in accord with the persistent inflammatory response observed in exposed humans (Yoon et al, 2013; Liu et al, 2015). The fact that COX-2 was mainly expressed by Type II cells provides support for the notion that these cells participate in inflammatory responses to tissue injury (Cheng et al, 2016). IL-6RA1 mRNA was also upregulated in the lung 21 d post-WTC dust exposure.…”

The Role of PGE2 in Alveolar Epithelial and Lung Microvascular Endothelial Crosstalk

“…We therefore hypothesize that these mechanisms by themselves are not sufficient to counteract the LPS-induced injury completely. Nonetheless, prostanoids produced from alveolar epithelial cells are protective, as a recent paper addressing acute lung injury in ATII-cell-specific COX-2 knockout mice reported increased levels of neutrophils and total cell counts in the bronchoalveolar lavage-fluid 49 and aggravated overall inflammation. Together with the fact that PGE 2 via EP4 receptor stimulation inhibits inflammation and neutrophil influx 20 , 50 , 51 , we provide further evidence that PGE 2 synthesized via the COX-2 pathway in ATII cells acts as an anti-inflammatory mediator.…”

Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases

“…The EVs are enriched for several miRNAs, including miR-630, which targets the pro-fibrotic genes that are upregulated in IPF fibroblasts. They also reported that administration of human MSC-derived EVs at day 14 in mice with pulmonary fibrosis induced by bleomycin significantly downregulated α-smooth muscle actin expression and decreased histopathological fibrosis, indicating the therapeutic effects of these vesicles on the established lung fibrosis through modification of the myofibroblastic phenotype [ 81 ].…”