Ethyl pyruvate protects rats from phosgene‐induced pulmonary edema by inhibiting cyclooxygenase2 and inducible nitric oxide synthase expression

Abstract

Phosgene is a poorly water-soluble gas penetrating the lower respiratory tract which can induce acute lung injury characterized by a latent phase of fatal pulmonary edema. Pulmonary edema caused by phosgene is believed to be a consequence of oxidative stress and inflammatory responses. Ethyl pyruvate (EP) has been demonstrated to have anti-inflammatory and anti-oxidative properties in vivo and in vitro. The potential therapeutic role of EP in phosgene-induced pulmonary edema has not been addressed so far. In the present study, we aim to investigate the protective effects of EP on phosgene-induced pulmonary edema and the underlying mechanisms. Rats were administered with EP (40 mg kg(-1)) and RAW264.7 cells were also incubated with it (0, 2, 5 or 10 µm) immediately after phosgene (400 ppm, 1 min) or air exposure. Wet-to-dry lung weight ratio (W:D ratio), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, cyclooxygenase2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and mitogen-activated protein kinases activities (MAPKs) were measured. Our results showed that EP treatment attenuated phosgene-induced pulmonary edema and decreased the level of NO and PGE(2) dose-dependently. Furthermore, EP significantly reduced COX-2 expression, iNOS expression and MAPK activation induced by phosgene. Moreover, specific inhibitors of MAPKs reduced COX-2 and iNOS expression induced by phosgene. These findings suggested that EP has a protective role against phosgene-induced pulmonary edema, which is mediated in part by inhibiting MAPK activation and subsequently down-regulating COX-2 and iNOS expression as well as decreasing the production of NO and PGE(2).

Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses

“…Flunixin meglumine probably reduced prostaglandin E 2 (PGE 2 ) synthesis and ameliorated the fever response to LPS. Ethyl pyruvate blocked COX‐2 expression and decreased PGE 2 synthesis in mouse mononuclear cells [29] and suppressed COX‐2 expression in equine mononuclear cells [16]. Effects of EP on COX‐1 are unknown, and may account for EP's poor response to LPS‐associated fever.…”

Systemic Administration of Rosmarinus officinalis Attenuates the Inflammatory Response Induced by Carrageenan in the Mouse Model of Pleurisy

“…Sakaguchi et al [37] demonstrated that administration of the NOS inhibitor L-NAME reduced NO x levels and exudation concentrations in carrageenan-induced pleurisy in rats. Also, Chen et al [38] demonstrated that in a model of phosgene-induced pulmonary edema in rats, there was a reduction of pulmonary edema and this effect was associated with a decrease of NO and PGE, as well as of cyclooxygenase-2 and inducible nitric oxide synthase levels, and activation of MAPKs. Interleukin-17A is an important proinflammatory cytokine that is involved in numerous immune and inflammatory responses by inducing the expression of other cytokines, chemokines, adhesion molecules, and growth factors [39].…”

Phosgene‐induced acute lung injury (ALI): differences from chlorine‐induced ALI and attempts to translate toxicology to clinical medicine

“…NOS‐2 inhibitors are highly efficacious in the development of phosgene‐induced ALI, especially when delivered by the inhalation route [96,97]. Data from rats (Fig.…”

“…NO is considered an important mediator of acute lung injury (ALI) and is endogenously produced by NO synthase 2 (NOS‐2), an enzyme upregulated in both ARDS patients and animal ALI models [98–100]. Recent studies have demonstrated that NOS‐2 is induced in rat lungs exposed to phosgene [96,101]. Hence, contemporaneous measurements of NO were thought to be an invaluable adjunct to exhaled CO 2 , as they may enable an integrated appreciation of the localized modulation of vascular tonus by NO suggestive of perfusion: ventilation imbalances.…”

“…Multiple approaches for drug‐related interventions, most of them anti‐inflammatory and sympathomimetic, have been examined [9, 19, 22, 23, 25, 26, 55, 96, 132, 133]; however, none of these drugs have found their way into the clinic. To the contrary, as could be expected for phosgene, anti‐inflammatory treatment with steroidal or non‐steroidal drugs was either ineffective or even aggravated phosgene‐induced ALI [21, 22, 44, 46].…”