Epidemiology and Etiology of Obstructive Sleep Apnea / 대한내과학회지

Obstructive sleep apnea (OSA) is one of common sleep disorders in western countries, affecting 4% of males and 2% of females. It is characterized by repeated obstruction of the upper airway during sleep, leading to intermittent hypoxemia, sympathetic activation, and sleep fragmentation. OSA is an independent risk factor for a range of medical problems, including cardiovascular disease, diabetes, depression, and cognitive dysfunctions. The etiology of OSA is complex and incompletely understood, but recent studies have shown that the development of OSA depends on the structure of the airway anatomy, the responsiveness of the upper airway dilator muscle to stimulation, and the stability of the respiratory control system. This review details the epidemiological and experimental evidence surrounding the associations between OSA and chronic diseases. Recent findings on the etiology of OSA will also be discussed.

Effects of Transglutaminase 2 Inhibition on Ventilator-Induced Lung Injury

This study was performed to examine the role of transglutaminase 2 (TG2) in ventilator-induced lung injury (VILI). C57BL/6 mice were divided into six experimental groups: 1) control group; 2) lipopolysaccharide (LPS) group; 3) lung protective ventilation (LPV) group; 4) VILI group; 5) VILI with cystamine, a TG2 inhibitor, pretreatment (Cyst+VILI) group; and 6) LPV with cystamine pretreatment (Cyst+LPV) group. Acute lung injury (ALI) score, TG2 activity and gene expression, inflammatory cytokines, and nuclear factor-kappaB (NF-kappaB) activity were measured. TG2 activity and gene expression were significantly increased in the VILI group (P < 0.05). Cystamine pretreatment significantly decreased TG2 activity and gene expression in the Cyst+VILI group (P < 0.05). Inflammatory cytokines were higher in the VILI group than in the LPS and LPV groups (P < 0.05), and significantly lower in the Cyst+VILI group than the VILI group (P < 0.05). NF-kappaB activity was increased in the VILI group compared with the LPS and LPV groups (P < 0.05), and significantly decreased in the Cyst+VILI group compared to the VILI group (P = 0.029). The ALI score of the Cyst+VILI group was lower than the VILI group, but the difference was not statistically significant (P = 0.105). These results suggest potential roles of TG2 in the pathogenesis of VILI.

The Effects of Nuclear Factor-kappa B Decoy Oligodeoxynucleotide on Lipopolysaccharide-Induced Direct Acute Lung Injury / 결핵및호흡기질환

BACKGROUND: The pathophysiologic mechanisms of early acute lung injury (ALI) differ according to the type of primary insult. It is important to differentiate between direct and indirect pathophysiologic pathways, and this may influence the approach to treatment strategies. NF-kappa B decoy oligodeoxynucleotide (ODN) is a useful tool for the blockade of the expression of NF-kappa B-dependent proinflammatory mediators and has been reported to be effective in indirect ALI. The purpose of this study was to investigate the effect of NF-kappa B decoy ODN in the lipopolysaccharide (LPS)-induced direct ALI model. METHODS: Five-week-old specific pathogen-free male BALB/c mice were used for the experiment. In the preliminary studies, tumor necrosis factor (TNF)-alpha, interleukine (IL)-6 and NF-kappa B activity peaked at 6 hours after LPS administration. Myeloperoxidase (MPO) activity and ALI score were highest at 36 and 48 hours, respectively. Therefore, it was decided to measure each parameter at the time of its highest level. The study mice were randomly divided into three experimental groups: (1) control group which was administered 50 microliter of saline and treated with intratracheal administration of 200 microliter DW containing only hemagglutinating virus of Japan (HVJ) vector (n=24); (2) LPS group in which LPS-induced ALI mice were treated with intratracheal administration of 200 microliter DW containing only HVJ vector (n=24); (3) LPS+ODN group in which LPS-induced ALI mice were treated with intratracheal administration of 200 microliter DW containing 160 microgram of NF-kappa B decoy ODN and HVJ vector (n=24). Each group was subdivided into four experimental subgroups: (1) tissue subgroup for histopathological examination for ALI at 48 hours (n=6); (2) 6-hour bronchoalveolar lavage (BAL) subgroup for measurement of TNF-alpha and IL-6 in BAL fluid (BALF) (n=6); (3) 36-hour BAL subgroup for MPO activity assays in BALF (n=6); and (4) tissue homogenate subgroup for measurement of NF-kappa B activity in lung tissue homogenates at 6 hours (n=6). RESULTS: NF-kappa B decoy ODN treatment significantly decreased NF-kappa B activity in lung tissues. However, it failed to improve the parameters of LPS-induced direct ALI, including the concentrations of tumor necrosis factor-alpha and interleukin-6 in BALF, myeloperoxidase activity in BALF and histopathologic changes measured by the ALI score. CONCLUSION: NF-kappa B decoy ODN, which has been proven to be effective in indirect models, had no effect in the direct ALI model.

The Effects of Ethyl Pyruvate on Lipopolysaccharide-induced Acute Lung Injury / 결핵및호흡기질환

BACKGROUND: Ethyl pyruvate (EP) is a derivative of pyruvate that has recently been identified by both various in vitro and in vivo studies to have antioxidant and anti-inflammatory effects. The aim of this study was to determine the effect of EP on lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: 5 weeks old, male BALB/c mice were used. ALI was induced by an intratracheal instillation of LPS 0.5mg/Kg/50microliter of saline. The mice were divided into the control, LPS, EP+LPS, and LPS+EP groups. In the control group, balanced salt solution was injected intraperitoneally 30 minutes before or 9 hours after the intratracheal instillation of saline. In the LPS group, a balanced salt solution was also injected intraperitoneally 30 minutes before or 9 hours after instillation the LPS. In the EP+LPS group, 40mg/Kg of EP was injected 30 minutes before LPS instillation. In the LPS+EP group, 40mg/Kg of EP was injected 9 hours after LPS instillation. The TNF-alpha and IL-6 concentrations in the bronchoalveolar lavage fluid (BALF), and that of NF-KappaB in the lung tissue were measured in the control, LPS and EP+LPS groups at 6 hours after instillation of saline or LPS, and the ALI score and myeloperoxidase (MPO) activity were measured in all four groups 24 and 48 hours after LPS instillation, respectively. RESULTS: The TNF-alpha and IL-6 concentrations were significantly lower in the EP+LPS group than in the LPS group (p<0.05). The changes in the concentration of these inflammatory cytokines were strongly correlated with that of NF-kappaB (p<0.01). The ALI scores were significantly lower in the EP+LPS and LPS+EP groups compared with the LPS group (p<0.05). In the EP+LPS group, the MPO activity was significantly lower than the LPS group (p=0.019). CONCLUSION: EP, either administered before or after LPS instillation, has protective effects against the pathogenesis of LPS-induced ALI. EP has potential theurapeutic effects on LPS-induced ALI.

The Role of Poly(ADP-ribose) Polymerase-1 in Ventilator-Induced Lung Injury / 결핵및호흡기질환

BACKGROUND: Reactive oxygen species (ROS) take center stage as executers in ventilator-induced lung injury (VILI). The protein with DNA-damage scanning activity, poly (ADP-ribose) polymerase-1 (PARP1), signals DNA rupture and participates in base-excision repair. Paradoxically,overactivation of PARP1 in response to massive genotoxic injury such as ROS can induce cell death through beta-nicotinamide adenine dinucleotide (NAD+) depletion, resulting in inflammation. The purpose of this study is to investigate the role of PARP1 and the effect of its inhibitor in VILI. METHODS: Forty-eight male C57BL/6 mice were divided into sham, lung protective ventilation(LPV), VILI, and PARP1 inhibitor (PJ34)+VILI (PJ34+VILI) groups. Mechanical ventilator setting for the LPV group was PIP 15 cmH2O + PEEP 3 cmH2O + RR 90/min + 2 hours. The VILI and PJ34+VILI groups were ventilated on a setting of PIP 40 cmH2O + PEEP 0 cmH2O + RR 90/min + 2 hours. As a PARP1 inhibitor for the PJ34+VILI group, 20 mg/Kg of PJ34 was treated intraperitoneally 2 hours before mechanical ventilation. Wet-to-dry weight ratio and acute lung injury (ALI) score were measured to determine the degree of VILI. PARP1 activity was evaluated by using an immunohistochemical method utilizing biotinylated NAD. Myeloperoxidase (MPO) activity and the concentration of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were measured in bronchoalveolar lavage fluid (BALF). RESULTS: In the PJ34+VILI group, PJ34 pretreatment significantly reduced the degree of lung injury, compared with the VILI group (p<0.05). The number of cells expressing PARP1 activity was significantly increased in the VILI group, but significantly decreased in the PJ34+VILI group (p=0.001). In BALF, MPO activity, TNF-alpha, IL-1beta, and IL-6 were also significantly lower in the PJ34+VILI group (all, p<0.05). CONCLUSION: PARP1 overactivation plays a major role in the mechanism of VILI. PARP1 inhibitor prevents VILI, and decreases MPO activity and inflammatory cytokines.