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Pulmonary Vascular Disease |

Effect of TNF-α Blockage on Pulmonary Vasculature in Chronic Intermittent Hypoxia-Induced Pulmonary Hypertension: An Animal Model of Obstructive Sleep Apnea FREE TO VIEW

Niwan Klinngam, MD; Akeruetai Suwannakin, MD; Sompol Sanguanrungsirikul, MD; Poonchavist Chantranuwatana, MD; Kittipong Maneechotesuwan, MD; Nattapong Jaimchariyatam, MD
Author and Funding Information

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand


Chest. 2014;146(4_MeetingAbstracts):856A. doi:10.1378/chest.1990527
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Abstract

SESSION TITLE: DVT/PE/Pulmonary Hypertension

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Wednesday, October 29, 2014 at 07:30 AM - 08:30 AM

PURPOSE: Tumor necrosis factor (TNF)-α is a key proinflammatory cytokine proved to be important in the development of pulmonary arterial hypertension (PAH), whereas its role in chronic intermittent hypoxia (CIH)-induced pulmonary hypertension (PH) as found in obstructive sleep apnea (OSA), has not been documented. We aim to assess the inflammatory and hemodynamic responses to CIH and examine the effects of etanercept, anti-TNF, in an animal model of OSA/CIH-induced PH.

METHODS: 30 Sprague-Dawley rats were randomly divided into 5 groups (6 rats/group) including 2 normoxic-groups, 2 CIH-groups and one normal group. Rats in CIH-groups were exposed to alternating cycles of normoxia (30 seconds at 21%O2) and hypoxia (30 seconds at 10%O2), for 8 h/day during the light phase for 28 days. Etanercept 0.4 mg/kg was given subcutaneously twice a week to one normoxic and one CIH-group. Serum concentration of TNF-α, interleukin-6 (IL-6) and lung tissue suspension of TNF-α, nuclear factor kappa-B (NF-kB) activity, and hypoxic inducible factor-1 (HIF-1) were measured. Hemodynamic and histopathological studies were completely executed. Data shown as mean±S.D. and p-value less than 0.05 defined as significance.

RESULTS: CIH induced significant increase in mean pulmonary arterial pressure (mPAP), pulmonary arterioles (50-100 microns in diameter) wall thickness and inflammation, and right ventricular hypertrophy (RVH), compared to normoxic-groups (p<0.05). However, there were no significant differences in mPAP and RVH between etanercept-treated and untreated CIH-group (p>0.05), but pulmonary arterioles wall thickness was significantly reduced in treated CIH-group (p=0.019). The serum and lung tissue suspension levels of TNF-α were significantly increased in untreated CIH-group by comparison with treated CIH-group (3.21±0.79 vs.1.93±0.90 pg/ml, and 7.05±2.47 vs. 4.33±1.51 pg/ml, respectively; p=0.01 and 0.02). There were no significant differences between the untreated and treated-CIH group concerning the lung tissue suspension of NF-kB, serum level of IL-6 and lung tissue of HIF-1 (p>0.05).

CONCLUSIONS: CIH induces inflammatory responses, increased mPAP, pulmonary vascular remodeling and RVH. Etanercept potentially inhibits vascular remodeling, early stage of PH, but fails to prevent established PH. Thus the hypoxia-induced PH is a highly complex process.

CLINICAL IMPLICATIONS: Study suggests the potential role of TNF-α and inflammation in CIH-induced PH progression but, in contrast to PAH, they appear not to be the important role.

DISCLOSURE: The following authors have nothing to disclose: Niwan Klinngam, Akeruetai Suwannakin, Sompol Sanguanrungsirikul, Poonchavist Chantranuwatana, Kittipong Maneechotesuwan, Nattapong Jaimchariyatam

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