Thromboxane A2 exacerbates acute lung injury via promoting edema formation

Abstract

Thromboxane A2 (TXA2) is produced in the lungs of patients suffering from acute lung injury (ALI). We assessed its contribution in disease progression using three different ALI mouse models. The administration of hydrochloric acid (HCl) or oleic acid (OA)+ lipopolysaccharide (LPS) caused tissue edema and neutrophil infiltration with TXA2 production in the lungs of the experimental mice. The administration of LPS induced only neutrophil accumulation without TXA2 production. Pretreatment with T prostanoid receptor (TP) antagonist attenuated the tissue edema but not neutrophil infiltration in these models. Intravital imaging and immunostaining demonstrated that administration of TP agonist caused vascular hyper-permeability by disrupting the endothelial barrier formation in the mouse ear. In vitro experiments showed that TP-stimulation disrupted the endothelial adherens junction, and it was inhibited by Ca2+ channel blockade or Rho kinase inhibition. Thus endogenous TXA2 exacerbates ALI, and its blockade attenuates it by modulating the extent of lung edema. This can be explained by the endothelial hyper-permeability caused by the activation of TXA2-TP axis, via Ca2+- and Rho kinase-dependent signaling.

L‐PGDS‐derived PGD2 attenuates acute lung injury by enhancing endothelial barrier formation

“…Another group showed that administration of a prostaglandin I 2 (PGI 2 ) receptor agonist prevented ALI symptoms in mouse ventilation-induced ALI [8]. Similarly, we and others reported that thromboxane A 2 (TXA 2 ) receptor inhibition attenuated HCl-and LPS-induced lung edema in mice [9,10]. Thus, PGs seem to have a multifaceted role in the pathophysiology of ALI, with both pro-inflammatory and anti-inflammatory functions.…”

Thromboxane-Induced α-CGRP Release from Peripheral Neurons Is an Essential Positive Feedback Loop in Capsaicin-Induced Neurogenic Inflammation

“…We observed that after capsaicin injection, mast cellederived TX is synthesized, which is known for its vasoconstrictive effects. However, previously, it was also shown that TX can also increase endothelial monolayer permeability in vitro (Kim et al, 2010;Klausner et al, 1994) and is a crucial mediator for edema formation in three different models of acute lung injury (Kobayashi et al, 2016). In addition, TX is rapidly hydrolyzed (t 1/2 approximately 30 seconds in aqueous solution at pH 7.4) to the stable derivative TXB 2 (Hamberg et al, 1975), which restricts the range of its effects on its direct neighborhood.…”

The effects of inhaled NO on plasma vasoactive factor and CTnI level in rabbits with acute massive pulmonary embolism

“…These activated platelets undergo degranulation to release TXA2 10,19,20 . AMPE leads to ischemia, hypoxia and acidosis in rabbits; H + promotes platelet degranulation to release TXA2, which further increases the formation and enlargement of emboli, thereby forming a vicious cycle [21][22][23] and…”