Association study of genetic variations of inflammatory biomarkers with susceptibility and severity of obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) increases health risks of cardiovascular disease and stroke. Both genetic factors and environmental exposures contribute to the occurrence of OSA. The purpose of this study was to determine the role of four functional inflammatory single nucleotide polymorphisms (SNPs) (VWF rs1063856, IL-6 rs1800796, TNF rs1800629, and CRP rs2794521) in the susceptibility and severity of OSA. METHODS: A case-control study of OSA among Chinese population was conducted. Genotyping was performed using ABI TaqMan SNP genotyping technique. RESULTS: We found VWF rs1063856 (OR = 1.50, 95% CIs = 1.10-2.04; p = 0.010), IL-6 rs1800796 (OR = 1.32, 95% CIs = 1.11-1.56; p = 0.002), TNF rs1800629 (OR = 1.44, 95% CIs = 1.13-1.83; p = 0.003), and CRP rs2794521 (OR = 1.27, 95% CIs = 1.04-1.55; p = 0.021) were all significantly associated with increased susceptibility of OSA, while VWF rs1063856 (OR = 1.75, 95% CIs = 1.18-2.62; p = 0.006), IL-6 rs1800796 (OR = 1.39, 95% CIs = 1.10-1.76; p = 0.006) were associated with the severity of OSA. CONCLUSIONS: Our study indicated that functional variants of inflammatory biomarkers could cause the occurrence of OSA and influence the severity of OSA. These findings further support that inflammatory cytokines were closely related to the occurrence and development of OSA.

Protective effects of the suppressed NF-κB/TLR4 signaling pathway on oxidative stress of lung tissue in rat with acute lung injury.

The pathogenesis of acute lung injury (ALI) is characterized by lung inflammation and lung oxidative stress. The study was conducted in order to investigate the effect toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) exhibited on oxidative stress in ALI. After the rats had been assigned into different groups, arterial blood, white blood cell (WBC), lung permeability index (LPI), wet/dry (W/D) ratio, TLR4 and NF-κB expression and superoxide dismutase (SOD), myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) were examined. Afterward, the correlation between the levels of TLR4 and NF-κB was determined. Decreased levels of PaO2 , SOD, MPO, and GSH accompanied by increased levels of PaCO2 , WBC number, LPI and W/D ratio, MDA and ROS, as well as TLR4 and NF-κB expressions in the ALI, ALI + NF-κB inhibitor, and ALI + phosphate buffer saline groups were found. Inhibition of NF-κB resulted in increased PaO2 and decreased PaCO2 levels, WBC number, and LPI and W/D ratio. Decreased expression of NF-κB increased SOD, GSH, and MPO, but decreased MDA and ROS. We also found that NF-κB inhibition resulted in the improvement of ALI in rats. TLR4 and NF-κB expressions were negatively correlated with levels of SOD, MPO, and GSH, and positively correlated with MDA and ROS levels. In summary, our findings provided evidence that inhibition of the TLR4/NF-κB signaling pathway decreases oxidative stress, thereby improving ALI. As a result, NF-κB signaling pathway has shown potential as a therapeutic target in ALI therapy.

Overexpressed long noncoding RNA CPS1-IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin-1ß expression via HIF1 transcriptional activity.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. This study was performed to examine the effects of long noncoding RNA CPS1 intronic transcript 1 (CPS1-IT) on PAH in rat models of obstructive sleep apnea (OSA) through regulating interleukin (IL)-1ß expression. The OSA models were induced in rats, for determination of the CPS1-IT expression. The binding of CPS1-IT and hypoxia-inducible factor 1 (HIF1) was verified. To analyze the effects of CPS1-IT on PAH, the overexpression vector of CPS1-IT and HIF1, shRNA against IL-1ß and pyrrolidine dithiocarbamate (PDTC, inhibitor of the NF-κB signaling pathway) were injected into rat models, respectively. The blood pressure and activity of biochemical indicators including nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), and lipid peroxide (LPO) were assessed. The expression of IL-1ß, HIF1, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and fibronectin (FN) was determined. The relationship of CPS1-IT to IL-1ß and NF-κB was evaluated. CPS1-IT was downregulated in the OSA rat model. Overexpressed CPS1-IT increased the activity of NO, NOS, and SOD as well as α-SMA expression, whereas decreasing LPO activity and expression of PCNA and FN, whereby PAH was suppressed. Notably, overexpressed CPS1-IT reduced IL-1ß expression through NF-κB signaling pathway via inhibiting the HIF1 transcriptional activity, suggesting a mechanism affecting PAH. To conclude, overexpressed CPS1-IT alleviated PAH in OSA by reducing IL-1ß expression, the mechanism of which was involved with inhibited HIF1 transcriptional activity and the NF-κB signaling pathway.

Correlations of inhaled NO with the cTnI levels and the plasma clotting factor in rabbits with acute massive pulmonary embolism.

PURPOSE: To investigate the correlation of inhaled nitric oxide (NO) on plasma levels of cardiac troponin I (cTnI) and von Willebrand factor (vWF), glycoprotein (GP) IIb/IIIa, granule membrane protein 140 (GMP-140) in rabbits with acute massive pulmonary embolism (PE). METHODS: Thirty apanese white rabbits were divided into 3 groups, thrombus were injected in model group (n = 10), NO were inhalated for 24 h after massive PE in NO group (n = 10), saline were injected in control group (n = 10). The concentrations of vWF, GP IIb/IIIa, GMP-140 and cTnI were tested at 4, 8, 12, 16, 20, and 24 h, Correlation analyses were conducted between cTnI and vWF, GP IIb/IIIa, and GMP-140 by Pearson's correlation. RESULTS: The concentration of cTnI and vWF, GP IIb/IIIa, and GMP-140 was increased in the model group, compared to control group. In the inhaled group, the concentrations of cTnI, vWF, GP IIb/IIIa, and GMP-140 were reduced compared to model group. There was a positive correlation between cTnI and vWF, GP IIb/IIIa, and GMP-140. CONCLUSION: Inhaled nitric oxide can lead to a decrease in levels of cardiac troponin I, von Willebrand factor, glycoprotein, and granule membrane protein 140, after an established myocardial damage, provoked by acute massive pulmonary embolism.

The effects of inhaled NO on plasma vasoactive factor and CTnI level in rabbits with acute massive pulmonary embolism1.

PURPOSE: To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices. METHODS: A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline). RESULTS: In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups. CONCLUSION: Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.

Correlations of inhaled NO with the cTnI levels and the plasma clotting factor in rabbits with acute massive pulmonary embolism

Abstract Purpose: To investigate the correlation of inhaled nitric oxide (NO) on plasma levels of cardiac troponin I (cTnI) and von Willebrand factor (vWF), glycoprotein (GP) IIb/IIIa, granule membrane protein 140 (GMP-140) in rabbits with acute massive pulmonary embolism (PE). Methods: Thirty apanese white rabbits were divided into 3 groups, thrombus were injected in model group (n = 10), NO were inhalated for 24 h after massive PE in NO group (n = 10), saline were injected in control group (n = 10). The concentrations of vWF, GP IIb/IIIa, GMP-140 and cTnI were tested at 4, 8, 12, 16, 20, and 24 h, Correlation analyses were conducted between cTnI and vWF, GP IIb/IIIa, and GMP-140 by Pearson's correlation. Results: The concentration of cTnI and vWF, GP IIb/IIIa, and GMP-140 was increased in the model group, compared to control group. In the inhaled group, the concentrations of cTnI, vWF, GP IIb/IIIa, and GMP-140 were reduced compared to model group. There was a positive correlation between cTnI and vWF, GP IIb/IIIa, and GMP-140. Conclusion: Inhaled nitric oxide can lead to a decrease in levels of cardiac troponin I, von Willebrand factor, glycoprotein, and granule membrane protein 140, after an established myocardial damage, provoked by acute massive pulmonary embolism.

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

Abstract Purpose: To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices. Methods: A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline). Results: In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups. Conclusion: Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.

The effect of nitric oxide inhalation on heart and pulmonary circulation in rabbits with acute massive pulmonary embolism.

The aim of the present study was to investigate the effect of nitric oxide inhalation (NOI) on cardiac troponin I (CTnI) levels and mean pulmonary arterial pressure (mPAP) in rabbits with acute massive pulmonary embolism (AMPE). Thirty rabbits were used as animal models for AMPE and received different treatments. A total of 4 h after successful modeling, the control group (CON, n=10) received conventional thrombolysis, whereas the treatment group (TRE, n=10) received conventional thrombolysis plus NOI. The experimental group (EXP, n=10) did not receive any treatments. Myocardial necrosis was pathologically confirmed in all 30 rabbits. In group EXP, the post-AMPE CTnI peak level was 0.42±0.12 µg/l, was achieved in 18.8±4.5 h and remained positive for 38.6±5.2 h (≥0.1 µg/l). These values were lower in group TRE when compared with those in groups CON and EXP (P<0.05). Group TRE exhibited significantly reduced mPAP at 24, 28, 32, and 34 h (P<0.05) when compared with group CON. AMPE-induced cardiac impairment was more severe in group EXP when compared with groups CON and TRE. The present findings indicated that the CTnI peak was significantly correlated with the corresponding mPAP. Furthermore, the results suggested NOI may reduce mPAP and CTnI peak levels, with protective effects against AMPE-induced myocardial damage in rabbits.