Mitochondrial separation protein inhibitor inhibits cell apoptosis in rat lungs during intermittent hypoxia.

Obstructive sleep apnoea (OSA) is a very common sleep and breathing disorder that occurs in worldwide. It is important to develop a more effective treatment for OSA to overcome lung cell apoptosis during intermittent hypoxia (IH). A mitochondrial separation protein inhibitor (Mdivi-1) has been demonstrated to be a powerful tool for inhibiting apoptosis. In the present study, the protective effect and possible mechanism of apoptosis in lung cells during IH was investigated using in vivo and in vitro experiments. Following IH exposure for 4 weeks, the lung tissues of Sprague Dawley rats exhibited interstitial lesions, while Mdivi-1 reduced these pulmonary interstitial lesions. B-cell lymphoma (Bcl)-2 mRNA and protein expression levels were decreased however caspase-3, caspase-9 and dynamin-related protein 1 (Drp-1) mRNA and protein expression levels were increased. Following Mdivi-1 intervention, Bcl-2 mRNA and protein expression levels were increased while caspase-3, caspase-9 and Drp-1 mRNA and protein expression levels were decreased (P<0.05). After exposure to IH for 12 h, the apoptosis rate of WTRL1 cells in rats increased gradually with the IH time (P<0.05). Bcl-2 mRNA and protein expression levels were decreased, whereas caspase-3, caspase-9, cytochrome C (Cyt-C) and Drp-1 mRNA levels were increased, and caspase-3, caspase-9 and Drp-1 protein expression levels were increased. After Mdivi-1 intervention, Bcl-2 mRNA and protein expression levels were increased but caspase-3, caspase-9, Cyt-C and Drp-1 mRNA levels were decreased along with caspase-9, Cyt-C and Drp-1 protein expression levels which were decreased (P<0.05). The results of the present study suggest that Mdivi-1 may be a potential agent for treating OSA because it inhibits the mitochondrial pathway and reduces apoptosis.

Volume-Targeted Versus Pressure-Limited Noninvasive Ventilation in Subjects With Acute Hypercapnic Respiratory Failure: A Multicenter Randomized Controlled Trial.

BACKGROUND: Volume-targeted noninvasive ventilation (VT-NIV), a hybrid mode that delivers a preset target tidal volume (VT) through the automated adjustment of pressure support, could guarantee a relatively constant target VT over pressure-limited noninvasive ventilation (PL-NIV) with fixed-level pressure support. Whether VT-NIV is more effective in improving ventilatory status in subjects with acute hypercapnic respiratory failure (AHRF) remains unclear. Our aim was to verify whether, in comparison with PL-NIV, VT-NIV would be more effective in correcting hypercapnia, hence reducing the need for intubation and improving survival in subjects with AHRF. METHODS: We performed a prospective randomized controlled trial in the general respiratory wards of 8 university-affiliated hospitals in China over a 12-month period. Subjects with AHRF, defined as arterial pH <7.35 and ≥7.25 and PaCO2 >45 mm Hg, were randomly assigned to undergo PL-NIV or VT-NIV. The primary end point was the decrement of PaCO2 from baseline to 6 h after randomization. Secondary end points included the decrement of PaCO2 from baseline to 2 h after randomization as well as outcomes of subjects (eg, need for intubation, in-hospital mortality). RESULTS: A total of 58 subjects were assigned to PL-NIV (29 subjects) or VT-NIV (29 subjects) and included in the analyses. The decrement of PaCO2 from baseline to 6 h after randomization was not statistically different between the PL-NIV group and the VT-NIV group (9.3 ± 12.6 mm Hg vs 11.7 ± 12.9 mm Hg, P = .48). There were no differences between the PL-NIV group and the VT-NIV group in the decrement of PaCO2 from baseline to 2 h after randomization (6.4 ± 12.7 mm Hg vs 5.0 ± 15.8 mm Hg, P = .71) as well as in the need for intubation (17.2% vs 10.3%, P = .70), and in-hospital mortality (10.3% vs 6.9%, P > .99). CONCLUSIONS: Regardless of whether a VT- or PL-NIV strategy is employed, it is possible to provide similar support to subjects with AHRF. (ClinicalTrials.gov registration NCT02538263.).

miR-138 inhibits proliferation by targeting 3-phosphoinositide-dependent protein kinase-1 in non-small cell lung cancer cells.

OBJECTIVE: Underlying mechanisms of non-small cell lung cancer (NSCLC) development remain poorly understood. miR-138 and 3-phosphoinositide-dependent protein kinase-1 (PDK1) have been reported to be involved in the genesis of NSCLC. The aim of this study was to investigate the role and mechanisms of miR-138 and PDK1 in human NSCLC cells. METHODS: The effect of miR-138 on proliferation of A549 lung cancer cells was first examined using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. The expression of PDK1 in A549 lung cancer cells was assessed by real-time polymerase chain reaction further. A luciferase reporter activity assay was conducted to confirm target association between miR-138 and 3' untranslated region (3'-UTR) of PDK1. Finally, the role of PDK1 on proliferation of A549 cells was evaluated by transefection of PDK1 small interfering RNA (siRNA). RESULTS: Proliferation of A549 lung cancer cells was suppressed by miR-138 in a concentration-dependent manner. Furthermore, miR-138 can bind to the 3'-UTR of PDK1 and downregulate expression of PDK1 at both mRNA and protein levels. Knockdown of PDK1 by siRNA significantly inhibits the proliferation of A549 lung cancer cells. CONCLUSIONS: These findings suggest that miR-138 as a potential tumor suppressor could inhibit cell proliferation by targeting PDK1 in NSCLC cells, which could be employed as a potential therapeutic target for miRNA-based NSCLC therapy.

Infliximab protects against pulmonary emphysema in smoking rats.

BACKGROUND: It is widely accepted that tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis of emphysema. This study aimed at investigating the protective effects of anti-TNF-α antibody, infliximab, in the development of emphysema induced by passive smoking in rats. METHODS: Thirty-nine rats were randomly divided into a normal control group (group 1), an emphysema group (group 2), and an infliximab-intervention group (group 3). Rat models of emphysema were established by exposure to cigarette smoking daily for 74 days. After 1 month, the infliximab intervention group was treated with infliximab via subcutaneous injection. The levels of TNF-α, IL-8 and vascular endothelial growth factor (VEGF) in bronchoalveolar lavage fluid (BALF) were measured with enzyme linked immunosorbent assay (ELISA). The number and classification of cells in the BALF were measured. Lung tissue sections stained by hematoxylin and eosin (HE) were observed, and mean linear intercept (MLI) and mean alveolar numbers (MAN) were measured. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) methods were used to examine the percentage of positive cells and distribution of apoptotic cells. RESULTS: The levels of TNF-α and IL-8 in BALF were higher in group 2 than in group 1 and group 3. The MLI was greater in group 2 than that in group 1 and group 3 while MAN was decreased. The concentration of VEGF in BALF of group 2 was significantly decreased as compared with group 1. The total cells and neutrophils number was significantly increased in group 2 as compared with group 1 and group 3, so was the percentage of neutrophils. The number of TUNEL positive cells in the alveolar septa was significantly increased in group 2 as compared with group 1 and group 3. CONCLUSION: Infliximab protects against cigarette smoking-induced emphysema by reducing airway inflammation, attenuating alveolar septa cell apoptosis and improving pathological changes.