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

Abstract

Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists.

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

“…For relative quantification of mRNA expression, real-time PCR was performed as described previously. 46…”

“…Interestingly, we found a profound down-and upregulation of 15-PGDH mRNA levels, respectively, after 24 hours (Fig 7, E) and regulation on protein level at 24 to 72 hours (Fig 7, F and H). Because A549 cells are a cancer cell line and partly differ in their behavior from alveolar epithelial cells, especially with regard to prostanoid synthesis, 46,62 we also transfected C57/Bl6 mice in vivo. Also in mouse lungs, the 218-5p mimetic caused a significant downregulation of 15-PGDH protein after 24 hours (Fig 7, G and I).…”

The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis

“…First, and expanding on an intrinsic ability described above, prostaglandins and COX-2-derived mediators also appear to promote the recovery of barrier function in both endothelial and epithelial cells. To illustrate, PGE2 release from LPSstimulated A549 epithelial cells, acting through PGE2 receptor EP4, has been shown to enhance microvascular endothelial cell barrier function [57]. Moreover, murine models indicate that COX-2 derived mediators are protective of acid-induced ALI and that selective inhibition delays resolution [58].…”

Cellular and Molecular Heterogeneity Associated with Vessel Formation Processes

“…Lung EC not only act as a selective and protective barrier, but also release angiocrine signals which may act in the pulmonary tissue homeostasis and during pathological conditions, by inducing a neo-alveologenesis in damaged lungs. Pulmonary capillary EC, for example, produce MMP-14 in response to a lung injury which in turn activates the EGF receptor (EGFR) that promotes proliferation of alveolar epithelial cells [ 227 – 229 ].…”