An analysis of fear inhibition and fear extinction in a sample of veterans with obstructive sleep apnea (OSA): Implications for co-morbidity with post-traumatic stress disorder (PTSD).

Obstructive sleep apnea (OSA) is a respiratory condition characterized by interrupted sleep due to repeated, temporary collapse of the soft tissue of the upper airway that can lead to a cascade of physiological and psychological adverse health outcomes. The most common therapeutic interventions for OSA patients include the application of continuous positive airway pressure (CPAP) which acts to keep the airway open and, as such, provides less interrupted and more restorative sleep. Improved sleep has been linked to more efficacious treatments for psychiatric conditions most notably those that include cognitive-behavioral elements, new learning, and memory consolidation. In the current study, we investigated the acquisition, inhibition, and extinction of conditioned fear in OSA patients, before and after CPAP therapy, using an established fear-potentiated startle paradigm. Patients with OSA displayed an intact ability to acquire, inhibit, and extinguish fear prior to CPAP treatment and this ability was significantly enhanced following CPAP usage. In addition, those patients with more severe OSA, as measured by apnea-hypopnea index (AHI), were more likely to show improved fear inhibition and extinction. Lastly, we observed impairments in discrimination between reinforced and nonreinforced conditioned stimuli, in the inhibition of fear, and in fear extinction in a subset of patients with OSA and co-morbid posttraumatic stress disorder (PTSD). These data suggest that evolving treatment algorithms for PTSD should address disrupted sleep problems prior to initiation of inhibition/extinction-based exposure therapies.

COVID-19: Review of a 21st Century Pandemic from Etiology to Neuro-psychiatric Implications.

COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients', families', and society's mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University's library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer's disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

Evaluation of human obstructive sleep apnea using computational fluid dynamics.

Obstructive sleep apnea (OSA) severity might be correlated to the flow characteristics of the upper airways. We aimed to investigate the severity of OSA based on 3D models constructed from CT scans coupled with computational fluid dynamics (CFD) simulations. The CT scans of seven adult patients diagnosed with OSA were used to reconstruct the 3D models of the upper airways and CFD modeling and analyses were performed. Results from the fluid simulations were compared with the apnea-hypopnea index. Here we show a correlation between a CFD-based parameter, the adjusted pressure coefficient (Cp*), and the respective apnea-hypopnea index (Pearson's r = 0.91, p = 0.004), which suggests that the anatomical-based model coupled with CFD could provide functional and localized information for different regions of the upper airways.

Oxidant stress mediates inflammation and apoptosis in ventilator-induced lung injury.

BACKGROUND AND OBJECTIVE: Ventilator-induced lung injury (VILI) leads to airway epithelial cell apoptosis and lung inflammation. High tidal volume ventilation in vivo has been shown to induce MIP-2 production, lung neutrophil sequestration and apoptotic airway cell death. This study aimed to determine the effect of N-acetylcysteine (NAC), a scavenger of oxygen radicals, on lung inflammation and apoptosis in an in vivo model of VILI. METHODS: Sprague-Dawley rats (n = 5 per group) were ventilated at low tidal volume (V(T) 7 mL/kg) or high tidal volume (V(T) 20 mL/kg) with or without administration of 140 mg/kg of intravenous NAC. Animals were ventilated for 30 min, 1 or 2 h, then allowed to recover for 2 h, at which time neutrophil infiltration, MIP-2, TNF-alpha and IL-6 in BAL fluid, as well as the percentage of apoptotic airway epithelial cells, were measured. RESULTS: Ventilation at V(T) 20 mL/kg increased oxidant release, as measured by serum isoprostane, and decreased lung glutathione, the major antioxidant in the lung. NAC treatment during ventilation at V(T) 20 mL/kg prevented the decrease in lung glutathione and significantly lowered serum isoprostane levels, neutrophil infiltration, cytokines in the BAL and apoptosis in the airways as compared with animals ventilated at V(T) 20 mL/kg without NAC (P < 0.05). CONCLUSIONS: These data point to an early role of oxidant-induced inflammation and apoptosis in VILI.

Nonadherence to CPAP Associated With Increased 30-Day Hospital Readmissions.

STUDY OBJECTIVES: The primary objective of this study was to determine if nonadherence to continuous positive airway pressure (CPAP) is associated with increased 30-day all-cause, cardiovascular-cause, and pulmonary-cause hospital readmissions. METHODS: Retrospective cohort study at a Veterans Affairs hospital of patients with obstructive sleep apnea (OSA) who were hospitalized from January 1, 2007 to December 31, 2015. Odds ratio of 30-day readmission was calculated for all-cause, cardiovascular-cause, and pulmonary-cause readmissions. Logistic regression model was used to evaluate odds of nonadherent versus adherent group while adjusting for age, sex, body mass index, living situation, race, comorbidities, and medication adherence. RESULTS: Out of 2,077 records reviewed, 345 patients (183 adherent and 162 nonadherent) met our inclusion criteria. The adherent group had a total of 215 initial admissions, and the nonadherent group had a total of 268 index admissions. Thirty-day all-cause readmission rate was significantly higher in the nonadherent group, with an adjusted odds ratio (OR) of 3.52 (95% confidence interval [CI], 2.04-6.08, P < .001). Thirty-day cardiovascular-cause readmission rate was significantly higher in the nonadherent group, with an adjusted OR of 2.31 (95% CI, 1.11-4.78, P = .024). Difference in 30-day pulmonary-cause readmissions was not statistically significant, with an adjusted OR of 3.66 (95% CI, 0.41-32.76, P = .25). CONCLUSIONS: Nonadherence to CPAP is associated with increased 30-day all-cause and cardiovascular-cause readmission in patients with OSA. Ensuring CPAP adherence is crucial in addressing general and cardiovascular-related healthcare utilization and morbidity in patients with OSA. COMMENTARY: A commentary on this article appears in this issue on page 161.

Characterization of soluble soybean (SSPS) polysaccharide and development of eco-friendly SSPS/TiO2 nanoparticle bionanocomposites.

This research aims to characterization of soluble soybean polysaccharide (SSPS) and development of a biodegradable SSPS nanocomposites prepared using various concentrations of TiO2 nanoparticles. 13C NMR suggested that backbone of SSPS is rhamnogalacturonan [1→4)-α-GalAp-(1/2)-α Rhap(1→]. Weight average molecular weight, number average molecular weight (Mn) and polydispersity index (PDI) of SSPS were found to be 2.54×106g/mol, 5.54×106g/mol, and 4.5, respectively. The intrinsic viscosity of SSPS (0.33) was lower than most of hydrocolloids. With increasing TiO2 concentration, the water solubility, moisture content and water-vapor permeability (WVP) of SSPS-based nanocomposite films decreased. TiO2 addition led to an increase in the melting temperature to a maximum of 132°C for the SSPS nanocomposite with 5wt% TiO2. With increasing TiO2 concentrations from 5 to 15wt%, the melting temperature declined from 24 to 19°C. There were no significant agglomerates when the TiO2 concentrations were increased to 5wt%; however, when the concentration reached 15wt%, agglomerations were observed. With addition of TiO2 nanoparticles, tensile strength increased but elongation at break decreased. SSPS-based nanocomposite films demonstrated a promising range of antimicrobial activity. The current research clearly introduces a new antimicrobial composite which is potentially useful to prevent and treat infections.

Sleep Architecture and Blood Pressure.

Different stages of sleep are associated with significant variability in cardiovascular function, which is mediated by marked changes in balance between 2 components of the autonomic system: parasympathetic and sympathetic. Autonomic control of circulation is essential in ensuring an adequate blood flow to vital organs through constant adjustments of arterial blood pressure, heart rate, and redistribution of blood flow. Fluctuations in components of the autonomic nervous system synchronize with electroencephalographic activity during arousal or different stages of sleep. As a result, these can lead to several cardiovascular consequences in those who have underlying heart disease or sleep-disordered breathing.

Rehabilitation of Cardiovascular Disorders and Sleep Apnea.

Obstructive sleep apnea (OSA) is present in more than 50% of patients referred to cardiac rehabilitation units. However, it has been under-recognized in patients after stroke and heart failure. Those with concurrent OSA have a worse clinical course. Early treatment of coexisting OSA with continuous positive airway pressure (CPAP) results in improved rehabilitation outcomes and quality of life. Possible mechanisms by which CPAP may improve recovery include decreased blood pressure fluctuations associated with apneas, and improved left ventricular function, cerebral blood flow, and oxygenation. Early screening and treatment of OSA should be integral components of patients entering cardiac rehabilitation units.

Eco-friendly soluble soybean polysaccharide/nanoclay Na+ bionanocomposite: Properties and characterization.

The impact of montmorillonite (MMT) as a nanofiller at different concentrations (5, 10, 15wt.%) on the physicochemical and functional properties of nanocomposite film based on soluble soybean polysaccharide (SSPS) was investigated. The results showed that an increase in MMT concentration was accompanied by a decrease in water solubility, thickness, and elongation at break. Furthermore, tensile strength increased when MMT concentration was increased to 10wt.%. Atomic force and scanning electron micrographs showed a significant agglomeration at MMT 15wt.%. With added MMT, the level of whiteness, greenness, and yellowness of SSPS film increased (P<0.05). Dynamic mechanical thermal analysis indicated that the storage modulus of nanocomposites increased when the MMT was increased to 10wt.%. Furthermore, Fourier transform infrared spectrophotometry demonstrated that no considerable changes occurred in the functional groups of the SSPS when MMT was added. Antimicrobial tests revealed that antibacterial and anti-mold activities were unlikely from reinforced nanocomposites.

Chitinase-3-like protein-1 (YKL-40) as a marker of endothelial dysfunction in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent disorder affecting 15-24% of adults and triples the risk for hypertension independent of other risk factors. The exact mechanisms of endothelial dysfunction and variable susceptibility to hypertension in OSA are not entirely clear. No biomarker to date has been found to be associated with hypertension in OSA. Chitinase-3-like protein-1(YKL-40) is a circulating moiety with roles in injury, repair and angiogenesis that is dysregulated in atherosclerosis and correlates with increased cardiovascular morbidity and mortality. We sought to determine the role of YKL-40, as a biomarker, for endothelial dysfunction and hypertension in OSA. METHODS: All subjects underwent polysomnography for suspected sleep-disordered breathing. Endothelial-dependent vasodilatory capacity was assessed using flow-mediated vasodilation (FMD). YKL-40 was measured in plasma using ELISA methodology. RESULTS: We studied 95 subjects in four groups according to OSA and hypertension status. FMD was markedly impaired in hypertensive OSA (8.0% ± 0.5 vasodilation) compared to normotensive OSA (13.5% ± 0.5, P <0.0001) and non-OSA with hypertension (10.5% ± 0.8, P <0.01) and without hypertension (16.1% ± 1.0, P <0.0001). YKL-40 was significantly elevated only in hypertensive OSA compared to other three groups and had a negative correlation with FMD (r=-0.37, P = 0.0008). Receiver operating characteristic (ROC) curve analysis for YKL-40 in predicting endothelial dysfunction had a sensitivity of 71% and a specificity of 64% with AUC = 0.68, 0.57 to 0.80, P = 0.004. CONCLUSIONS: Elevated circulating levels of YKL-40 are observed in only hypertensive OSA and have a significant negative correlation with endothelial function. This specificity suggests YKL-40 could be a potential biomarker for endothelial dysfunction in OSA.

Increased plasma YKL-40/chitinase-3-like-protein-1 is associated with endothelial dysfunction in obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) is a common disorder affecting 15-24% of the adults and is associated with increased risk of hypertension and atherosclerosis. The exact mechanisms underlying hypertension in OSA are not entirely clear. YKL-40/Chitinase-3-like protein-1 is a circulating moiety with roles in injury, repair and angiogenesis that is dysregulated in atherosclerosis and a number of other diseases. We sought to determine the role of YKL-40 in endothelial dysfunction and hypertension in OSA. METHODS: We studies 23 normotensive OSA (N-OSA) and 14 hypertensive OSA (H-OSA) without diabetes and apparent cardiovascular disease. Endothelial-dependent nitric oxide-mediated vasodilatory capacity was assessed by flow-mediated vasodilation (FMD). YKL-40, vascular endothelial growth factor (VEGF) and the soluble form of VEGF receptor-1 or sFlt-1 were measured in plasma using ELISA methodology. RESULTS: N-OSA subjects aged 49.1 ± 2.3 years and H-OSA aged 51.3 ± 1.9 years with BMI 36.1 ± 1.6 and 37.6 ± 1.9 kg/m(2), respectively. The apnea-hypopnea index (AHI) was 41 ± 5 events/hr in N-OSA and 46 ± 6 in H-OSA with comparable degree of oxygen desaturations during sleep. FMD was markedly impaired in H-OSA (8.3% ± 0.8) compared to N-OSA (13.2% ± 0.6, P<0.0001). Plasma YKL-40 was significantly elevated in H-OSA (55.2 ± 7.9 ng/ml vs. 35.6 ± 4.2 ng/ml in N-OSA, P = 0.02) and had an inverse relationship with FMD (r = -0.52, P = 0.013). There was a significant positive correlation between sFlt-1/VEGF, a measure of decreased VEGF availability, and YKL-40 (r = 0.42, P = 0.04). CONCLUSION: The levels of plasma YKL-40 were elevated in H-OSA group and inversely correlated with the endothelial-dependent vasodilatory capacity whereas there was a positive correlation between sFlt-1/VEGF and YKL-40. These findings suggest that YKL-40 is dysregulated, in part, due to perturbation of VEGF signaling, and may contribute to endothelial dysfunction and hypertension in OSA.

Recurrent hydrothorax and surgical diaphragmatic repair: report of 2 cases and review of the literature.

BACKGROUND: Pleural effusions may result from intra-abdominal processes and sometimes present with dramatic clinical consequences. We present 2 cases of recurrent hydrothorax requiring surgical repair of diaphragmatic defects and describe when surgery may be the best treatment modality. PATIENT 1: : A 63-year-old man with end-stage renal disease requiring peritoneal dialysis presented with dyspnea on exertion that progressed to cardiac arrest. He was found to have a tension hydrothorax that was initially stabilized with thoracentesis and tube thoracostomy. He eventually underwent surgical repair of fenestrations with complete resolution of his effusion. PATIENT 2:: A 52-year-old man with recurrent hydrothorax in the context of hepatitis C cirrhosis and hepatocellular carcinoma following radiofrequency ablation to his liver had recurrent admissions with dyspnea and a large pleural effusion. When medical therapy failed, he underwent surgical repair of a large diaphragmatic defect. CONCLUSIONS: Hydrothorax related to peritoneal dialysis or cirrhosis may cause life-threatening scenarios in which medical management may stabilize the patient. Ultimately, surgical corrections of diaphragmatic defects may be necessary for definitive management in selected patients. Although these scenarios are rare, clinicians should be aware of these possibilities as early collaboration between medical and surgical services is essential for optimal patient care.

Endothelial dysfunction and hypertension in obstructive sleep apnea - Is it due to intermittent hypoxia?

BACKGROUND: Obstructive sleep apnea (OSA) is a prevalent disorder causing hypertension. Endothelial dysfunction appears to underlie development of hypertension. It is not known whether hypoxia during sleep is necessarily the prerequisite process for endothelial dysfunction and hypertension in OSA. We therefore examined the relationship between endothelial-dependent vasodilatory capacity, hypoxia and circulating angiogenesis inhibitors in OSA. METHODS AND RESULTS: We studies 95 subjects with and without OSA and hypertension. Endothelial-dependent vasodilation was assessed using brachial artery flow-mediated vasodilation method (FMD). Plasma angiogenesis inhibitors, endoglin (sEng) and fms-like tyrosine kinase-1 (sFlt-1), were measured using ELISA. The apnea-hypopnea indexes were 41 ± 5 and 48 ± 4 events/hr in normotensive OSA (N-OSA) and hypertensive OSA (H-OSA), respectively, indicating severe OSA. The sleep time spent with SaO2 < 90% (T < 90%) were 34 ± 8 and 40 ± 9 min, respectively. FMD was markedly impaired in H-OSA (8.0% ± 0.5) compared to N-OSA (13.5% ± 0.5, P < 0.0001), H-non-OSA (10.5% ± 0.8, P < 0.01), and N-non-OSA (16.1% ± 1.0, P < 0.0001). There was no correlation between T < 90% and FMD. Both OSA groups had elevated levels of sFlt-1 (62.4 ± 5.9 and 63.9 ± 4.7 pg/ml) compared to N-non-OSA (32.1 ± 6.5, P = 0.0008 and P = 0.0004, respectively) and H-non-OSA (41.2 ± 7.0, P < 0.05 and P = 0.03, respectively). In contrast, sEng was only elevated in H-OSA (4.20 ± 0.17 ng/ml) compared with N-OSA (3.64 ± 0.14, P = 0.01) and N-non-OSA (3.48 ± 0.20, P = 0.01). There was a modest but statistically significant inverse correlation between sEng and FMD in only H-OSA group (r = -0.38, P < 0.05). CONCLUSION: These data show that patients with OSA and hypertension have marked impairment of FMD, independent of hypoxia exposure, which is associated with increased sEng.

Activation of heme oxygenase and suppression of cGMP are associated with impaired endothelial function in obstructive sleep apnea with hypertension.

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent disorder that increases the risk of systemic hypertension and cardiovascular diseases. Heme oxygenase (HO) has been shown to be upregulated in patients with OSA and its overexpression in mice causes hypertension. End products of HO are carbon monoxide (CO) and bilirubin. CO exerts a pleiotropic action on vasoregulation. Despite high prevalence and incident of hypertension in OSA, its pathophysiology is not well-understood, particularly in regard to varying susceptibility of patients to hypertension. We investigated the role of HO in endothelial dysfunction and hypertension in OSA. METHODS: We determined flow-mediated vasodilatation (FMD) as a measure of endothelial-dependent vasodilatory capacity, exhaled CO, bilirubin, and guanosine 3',5'-cyclic monophosphate (cGMP) in 63 subjects with OSA (normotensive 27, hypertensive 36) and in 32 subjects without OSA (normotensive 19, hypertensive 13). RESULTS: Hypertensive OSA demonstrated marked impairment in FMD (8.0 ± 0.5% vasodilatation) compared to 10.5 ± 0.8% in hypertensives non-OSA (P < 0.01) and 13.5 ± 0.5% in normotensive OSA (P < 0.001) and 16.1 ± 1.1% in normotensive non-OSA (P < 0.0001). HO was upregulated and plasma nitric oxide (NO) was significantly increased in hypertensive OSA compared to normotensive OSA and hypertensive non-OSA. Conversely, serum cGMP was markedly decreased in hypertensive OSA (12.9 ± 1.8 pmol/ml vs. 20.6 ± 3.7 in normotensive OSA, P = 0.032). There was an inverse relationship between FMD and CO and bilirubin concentrations (r = 0.43, P = 0.0001 and r = 0.28, P = 0.01, respectively). CONCLUSIONS: These data show that increased CO in the setting of elevated NO concentrations is associated with decreased cGMP, impaired FMD, and hypertension in patient with OSA.

Characteristics of refractory vs. medically controlled epilepsy patients with obstructive sleep apnea and their response to CPAP treatment.

UNLABELLED: Obstructive sleep apnea (OSA) commonly coexists with epilepsy, and treatment of OSA may decrease seizure frequency. However, it is unclear whether patients with medically refractory epilepsy have a higher incidence of OSA compared with well-controlled epilepsy patients and whether the two groups carry different risk factors. PURPOSE: This study aimed to investigate the presence of OSA in patients with refractory vs. well-controlled epilepsy and their associated risk factors. We also assessed the benefits of treatment of OSA with continuous positive airway pressure (CPAP) in refractory epilepsy patients. METHODS: We retrospectively reviewed data from patients who presented to the Jacobs Neurological Institute Comprehensive Epilepsy Center of University at Buffalo from 2007 to 2010. RESULTS: There is a tendency for much higher incidence of OSA in our epilepsy population compared with the general population (15.2% vs. 4.41%). For patients with well-controlled epilepsy, older age, male gender, and higher seizure frequency were predictors of a diagnosis of OSA. However, in medically refractory epilepsy patients, diabetes and snoring predicted a diagnosis of OSA. Treatment of OSA with CPAP in refractory epilepsy patients improved their seizure control (p<0.02). CONCLUSION: This study confirms that OSA is common in epilepsy patients and treatment of OSA can improve seizure control in medically refractory cases. Patients with refractory epilepsy who have diabetes are more likely to have OSA.

Overnight rostral fluid shift in obstructive sleep apnea: does it affect the severity of sleep-disordered breathing?

BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder with multifactorial pathogenesis. It has been proposed that rostral fluid displacement contributes to the pathogenesis of OSA. We hypothesized that if fluid shift is an important factor in OSA, then it would be more severe during the second one-half of the night when there is maximally displaced fluid rostrally. METHODS: We prospectively enrolled 135 patients who underwent polysomnography. Neck and leg circumferences were measured to determine rostral fluid shift in recumbent position before and after sleep study. Breathing disturbance index (BDI) was derived for non-rapid eye movement sleep during the first and second one-half of the night in the same position. RESULTS: Sixty-five patients with demonstrable rostral fluid shift overnight were included in the analyses. Thirty-two (age, 52.5 ± 2.2 years) had OSA with a mean BDI of 27 ± 3/h (range, 5-80/h), whereas the other 33 with mainly upper airway resistance syndrome (age, 48.7 ± 2.4 years) had a BDI of 13 ± 2/h. Patients in both groups were obese. There was a statistically significant increase in neck circumference in patients with OSA (41.5 ± 0.8 to 42.6 ± 0.7 cm, P < .0001) and without OSA (38.6 ± 0.6 to 40.2 ± 0.6 cm, P < .0001) overnight, with concomitant decreases in leg circumferences. In spite of the fluid shift, BDI did not change (18 ± 3/h and 20 ± 3/h) between the first and second one-half of the night. CONCLUSIONS: There is a significant fluid shift rostrally to the neck overnight in patients with and without OSA. However, this fluid shift is not associated with worsening of OSA, thus making it unlikely that fluid displacement is a contributing factor in the pathogenesis or severity of OSA.

Polysomnography.

Polysomnography (PSG) is an essential tool for diagnosis of a variety of sleep disorders. The results of PSG should be interpreted in the context of a patient's history and medications and observation in the sleep laboratory. As new technologies evolve, it is expected that the field will evolve. Further work is needed to determine if computerized scoring, with or without human revision, may reliably replace visual scoring in normal and abnormal sleep. Improved techniques to measure and quantify sleep itself will allow for more meaningful assessment of sleep disruption that can lead to the recognition of new disorders and better predictions of the outcomes of these disorders.

Intracellular glutathione in stretch-induced cytokine release from alveolar type-2 like cells.

OBJECTIVE: Ventilator-induced lung injury (VILI) is characterized by release of inflammatory cytokines, but the mechanisms are not well understood. We hypothesized that stretch-induced cytokine production is dependent on oxidant release and is regulated by intracellular glutathione (GSH) inhibition of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding. METHODOLOGY: Type 2-like alveolar epithelial cells (A549) were exposed to cyclic stretch at 15% strain for 4 h at 20 cycles/min with or without N-acetylcysteine (NAC) or glutathione monoethylester (GSH-e) to increase intracellular GSH, or buthionine sulfoximine (BSO), to deplete intracellular GSH. RESULTS: Cyclic stretch initially caused a decline in intracellular GSH and a rise in the levels of isoprostane, a marker of oxidant injury. This was followed by a significant increase in intracellular GSH and a decrease in isoprostane. Stretch-induced IL-8 and IL-6 production were significantly inhibited when intracellular GSH was further increased by NAC or GSH-e (P < 0.0001). Stretch-induced IL-8 and IL-6 production were augmented when intracellular GSH was depleted by BSO (P < 0.0001). NAC blocked stretch-induced NF-kappa B and AP-1 binding and inhibited IL-8 mRNA expression. CONCLUSIONS: We conclude that oxidant release may play a role in lung cell stretch-induced cytokine release, and antioxidants, which increase intracellular GSH, may protect lung cells against stretch-induced injury.

Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-kappaB-inducing kinases.

Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch-induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun NH2-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min-2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of stress-activated protein kinase (SEK-1), a dominant-negative mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-kappaB and activator protein (AP)-1 was blocked by NF-kappaB inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-kappaB-inducing kinase (NIK) activation, and inhibition of NF-kappaB attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch-induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-kappaB and was dependent on JNK and NIK activation, respectively.