Etanercept Reduces Late Endotoxin-Induced Pulmonary Hypertension in the Pig

Abstract

To evaluate whether etanercept, a tumor necrosis factor (TNF)-blocking agent, may counteract hemodynamic deterioration in endotoxemic shock, we designed a prospective, randomized placebo-controlled trial with parallel groups, consisting of 13 pigs aged 10-14 weeks receiving general anesthesia. Five pigs were given 25 mg of etanercept, 1 h before the start of a 4-h continuous infusion of endotoxin. Another 5 pigs were given the corresponding volume of saline, 1 h before the start of a 4-h continuous infusion of endotoxin. Three pigs were given 25 mg of etanercept, 1 hr before the start of a 4-h continuous infusion of saline. At 1 h of endotoxemia, mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) increased identically in both groups of pigs receiving endotoxin. Thereafter, two distinct different patterns in hemodynamics were observed. TNF-blocked pigs showed significantly lower MPAP and PVRI compared to controls. In the etanercept-treated endotoxemic pigs, Doppler analysis of the diastolic mitral inflow demonstrated a significantly increased E/A-ratio (early mitral wave inflow was divided by the atrial wave) at 2 h. The TNFblocking agent etanercept normalized two hemodynamic features of endotoxin-induced septic shock in pigs: (1) the sustained pulmonary hypertension and (2) diastolic dysfunction.

Effects of florfenicol on early cytokine responses and survival in murine endotoxemia

“…Several attempts in controlling septic shock are going on by intervening TNF pathway, including protein reagents, such as TNF antibody and Enbrel, a TNF receptor fusion protein [27]; as well as small molecule inhibitor of TNF, such as TACE inhibitors (TNF-α converting Enzyme) [28]. In addition, a few reports indicate that ciprofloxacin inhibits TNF production targeted at binding TLR4 without any signaling function, resulting in blocking LPS/TLR pathway, and attenuating TNF production.…”

Inflammatory cytokines in pulmonary hypertension

“…It could be demonstrated that the PDH activity was significantly decreased in cells treated with TNF-α, while MCT-treated rats that were injected with Etanercept (a TNF-α antagonist) were found to be protected from development of PAH [64]. In another study, rats treated with a TNF-α blocker (rhTNFRFc) showed some amelioration in pulmonary hemodynamics, right ventricular hypertrophy and pulmonary inflammation [65] and in pigs with endotoxemic-shock-induced pulmonary hypertension, Etanercept was able to lower both pulmonary arterial pressure and pulmonary vascular resistance compared to pigs without Etanercept therapy [66]. Other studies using TNF-α - antagonists, however, could not confirm an improvement of pulmonary hypertension [67,68].…”

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

“…Of note, transgenic mice overexpressing TNFα in the lung develop spontaneous PAH13 and lung TNFα expression is elevated in rats or dogs with pulmonary hypertension induced with monocrotaline (MCT-PAH) or a high flow left-to-right shunt141516. Etanercept, a soluble TNF-receptor II dimer, prevents and reverses MCT-PAH in rats17 and reverses PAH in endotoxemic pigs18. Moreover, TNFα suppresses BMPR-II levels in aortic endothelial cells19.…”