Enhanced release of thromboxane A₂ after exposure of human airway epithelial cells to meconium

Abstract

Meconium aspiration syndrome (MAS) is a cause of significant morbidity and mortality in the perinatal period. Despite the clinical relevance of MAS, its pathogenesis is poorly understood. Epithelial cell-derived prostanoids are involved in the regulation of several cellular functions within the lung, including the control of tone and reactivity of airway and vascular smooth muscle. In this study, we evaluated whether exposure to meconium affects the metabolic function of human airway epithelial cells. Monolayers of A549 cells, a transformed human epithelial cell line, were incubated with various concentrations of meconium. Control cells were incubated with serum-free medium in a similar manner. The supernatant fluid was removed at various time points and assayed for thromboxane A(2) (TXA(2)) production. The latter was accomplished by measuring its immediate and stable metabolite thromboxane B(2), using an enzyme-linked immunosorbent assay (ELISA). In selected experiments, the modulatory effects of indomethacin (10(-6) M), dexamethasone (10(-6) M), and L-nitroarginine methyl ester (L-NAME, 10(-6) M) on TXA(2) production were evaluated. Results were expressed in terms of pg/mg protein (mean +/- SE). We found that exposure to meconium produced a significant release of TXA(2) from A549 cells. Indomethacin, dexamethasone, and in part, L-NAME inhibited meconium-induced release of TXA(2). Our findings demonstrate that meconium enhances the production of thromboxanes from A549 cells, suggesting that airway epithelial cells and their metabolic products may play an important role in the pathogenesis of MAS.

Dexamethasone Alleviates Meconium‐Induced Airway Hyperresponsiveness and Lung Inflammation in Rabbits

“…19 The airway narrowing in MAS is caused not only by mechanical obstruction by aspirated meconium, but also by peribronchial edema due to the action of various inflammatory mediators. The release of these mediators, including arachidonic acid metabolic products from activated cells during inflammation, modulates the smooth muscle tone and its responses to contractile mediators, 20,21 and may thus contribute to airway hyperreactivity. Whereas airway inflammation is usually associated with increased in vitro smooth muscle reactivity, 17,22 we tested in vitro airway reactivity in rabbits with meconium aspiration.…”

Inflammation in Meconium Aspiration Syndrome: Targets for Pharmacological Modulation

“…Recently, a non-selective inhibitor of NOS NG-nitro-Larginine-methyl-ester (L-NAME) inhibited meconiuminduced release of NO and TXA 2 from epithelial cells [22,33], while L-NAME and selective iNOS inhibitor aminoguanidine decreased airway reactivity in antigen-or chemicallyinduced airway hyperreactivity [31]. Finally, reducing NO clearance by superoxide, superoxide dismutase (SOD) may enhance the response to NO [114].…”

“…elevated levels of TXA 2 are in MAS associated with pulmonary hypertension and edema formation [21]. Increased release of TXA 2 from epithelial cells after in vitro meconium exposure [22] and COX-2 expression in rats with meconium aspiration [23] were found. The 5-lipooxygenase products contribute to pulmonary vasoconstriction, airway hyperreactivity, and increased vascular permeability.…”

The role of complement in meconium aspiration syndrome

“…24 In addition, meconium has been shown capable of upregulating cyclooxygenase-2 mRNA expression in rat lungs, a process that is inhibited by dexamethasone, but not indomethacin 25 and enhance the release of thromboxane-A 2 in human airway epithelial cells. 26 Finally, apoptosis associated with meconium 22,27,28 could be inhibited by angiotensin II receptor blockade. 27 The effect of meconium on oxidative burst (release of reactive oxygen species) has been difficult to interpret.…”