Monomethyl fumarate attenuates lung Ischemia/Reperfusion injury by disrupting the GAPDH/Siah1 signaling cascade.

Monomethyl fumarate (MMF), a potent anti-inflammatory agent used to treat multiple sclerosis, has demonstrated efficacy in various inflammatory and ischemia/reperfusion (IR) models; however, its impact on IR-induced acute lung injury (ALI) has not been explored. We investigated, for the first time, whether MMF attenuates lung IR injury through inhibition of the GAPDH/Siah1 signaling pathway. Rats were subjected to IR injury using an isolated perfused lung model, and proximity ligation assays were employed to evaluate the presence and distribution of the GAPDH/Siah1 complex. In vitro studies involved pretreating human primary alveolar epithelial cells (HPAECs) with MMF and/or inducing GAPDH overexpression or silencing, followed by exposure to hypoxia-reoxygenation. The findings revealed significantly reduced lung damage indicators, including edema, proinflammatory cytokines, oxidative stress and apoptosis, in MMF-treated rats. Notably, MMF treatment inhibited GAPDH/Siah1 complex formation and nuclear translocation, indicating that disruption of the GAPDH/Siah1 cascade was the primary cause of these improvements. Our in vitro studies on pretreated HPAECs corroborate these in vivo findings, further strengthening this interpretation. Our study results suggest that the protective effects of MMF against lung IR injury may be attributed, at least in part, to its ability to disrupt the GAPDH/Siah1 signaling cascade, thereby attenuating inflammatory and apoptotic responses. Given these encouraging results, MMF has emerged as a promising therapeutic candidate for the management of lung IR injury.

Molecular Hydrogen as a Promising Therapy Could Be Linked With Increased Resting Treg Cells or Decreased Fas+ T Cell Subsets in a IgG4-PF-ILD Patient: A Case Report.

BACKGROUND/AIM: Progressive fibrosing interstitial lung disease (PF-ILD) refers to a group of chronic lung conditions commonly associated with immunoglobulin G4-related disorders. It is characterized by progressive scarring (fibrosis) within the pulmonary interstitium, resulting in respiratory failure and early mortality. Some patients do not respond to standard therapeutic interventions. Numerous studies have confirmed the anti-inflammatory and antioxidant properties of molecular hydrogen in various disease models. CASE REPORT: In this report, we present a case study of an 85-year-old female diagnosed with suspected IgG4-related PF-ILD complicated by hospital-acquired pneumonia. On the fourth day of hydrogen-assisted therapy, a noticeable improvement in lung infiltrations was observed in chest X-rays as the patient gradually progressed towards weaning off mechanical ventilation. To assess treatment responses, we compared immune phenotypes before and after hydrogen treatment. A marked increase was observed in resting regulatory T cell levels after treatment, accompanied by a notable decrease in Fas+ helper T cell and cytotoxic T cell subtypes. CONCLUSION: This case study highlights the effectiveness of hydrogen-assisted therapy in managing PF-ILD complicated by pneumonia, warranting further research in the future.

Alda-1 ameliorates air embolism-induced acute lung injury.

OBJECTIVE: Evidence suggests that aldehyde dehydrogenase 2 (ALDH2) offers protection against damage caused by oxidative stress in diverse rodent models. Nonetheless, the effect of Alda-1, a compound that activates ALDH2, on acute lung injury (ALI) induced by air embolism (AE) remains unclear. The objective of this study was to explore the protective effects of Alda-1 in ALI induced by AE. METHODS: A rat model of in situ isolated perfused lung was established to investigate AE-induced ALI. Air was infused into the pulmonary artery at 0.25 mL/min for 1 minute. Before inducing AE, different doses (10, 20, or 30 mg/kg) of Alda-1 were given through intraperitoneal injection. Pathological changes in lung tissue were assessed using hematoxylin-eosin staining. We performed Western blot analysis to assess the protein levels of ALDH2,4-hydroxy-trans-2-nonenal (4-HNE), Bcl-2, caspase-3, phosphatidylinositol 3-kinase (PI3K), Akt, IκB-α, and nuclear NF-κB. RESULTS: Notably, AE results were demonstrated as harmful to the lungs, which is evidenced by intensified lung edema and disruption of lung tissue structure. Furthermore, AE caused a decrease in ALDH2 expression, increased accumulation of 4-HNE and MDA, infiltration of neutrophils, increased production of inflammatory cytokines, apoptosis, and upregulation of the PI3K/Akt and NF-κB signaling pathways within the lungs. Administration of a 20 mg/kg dose of Alda-1 alleviated the detrimental effects induced by AE. CONCLUSION: Alda-1 shows promise in mitigating AE-induced ALI, possibly through the upregulation of ALDH2 expression and suppression of the PI3K/Akt and NF-κB signaling pathways. Further research is warranted to validate these findings and to explore their translational potential in human subjects.

Targeting Rev-Erbα to protect against ischemia-reperfusion-induced acute lung injury in rats.

BACKGROUND: The dysregulation of local circadian clock has been implicated in the pathogenesis of a broad spectrum of diseases. However, the pathophysiological role of intrinsic circadian clocks Rev-Erbα in ischemia-reperfusion (IR)-induced acute lung injury (ALI) remains unclear. METHODS: The IR-ALI model was established by subjecting isolated perfused rat lungs to 40 min of ischemia followed by 60 min of reperfusion. Rats were randomly assigned to one of six groups: control, control + SR9009 (Rev-Erbα agonist, 50 mg/kg), IR, and IR + SR9009 at one of three dosages (12.5, 25, 50 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed. In vitro experiments utilized mouse lung epithelial cells (MLE-12) exposed to hypoxia-reoxygenation (HR) and pretreated with SR9009 (10 µM/L) and Rev-Erbα siRNA. RESULTS: SR9009 exhibited a dose-dependent reduction in lung edema in IR-ALI. It significantly inhibited the production of TNF-α, IL-6, and CINC-1 in BALF. Moreover, SR9009 treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, a SR9009 mitigated IR-induced apoptosis and mitogen-activated protein kinase (MAPK) activation in injured lung tissue. Finally, treatment with Rev-Erbα antagonist SR8278 abolished the protective action of SR9009. In vitro analyses showed that SR9009 attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR, and these effects were significantly abrogated by Rev-Erbα siRNA. CONCLUSIONS: The findings suggest that SR9009 exerts protective effects against IR-ALI in a Rev-Erbα-dependent manner. SR9009 may provide a novel adjuvant therapeutic approach for IR-ALI.

Corrigendum: Cell volume restriction by mercury chloride reduces M1-like inflammatory response of bone marrow-derived macrophages.

[This corrects the article DOI: 10.3389/fphar.2022.1074986.].

Risk of secondary stroke subsequent to restarting aspirin in chronic stroke patients suffering from traumatic brain injury in Taiwan.

Traumatic brain injury (TBI) is a silent epidemic that has been easily ignored. The safety and efficacy of restarting antiplatelet therapy after encountering traumatic brain injury (TBI) events remain a challenge. We explored the outcomes of restarting aspirin use on secondary stroke and mortality in patients with chronic stroke 4 weeks after suffering from a TBI episode in Taiwan. This study analyzed data from the National Health Insurance Research Database from January 2000 to December 2015. Overall, 136,211 individuals diagnosed with chronic stroke who suffered from acute TBI and received inpatient service were enrolled. The study outcomes were a competing risk of secondary stroke (ischemic and hemorrhagic) hospitalization and all-cause mortality. We identified a case group of 15,035 patients with chronic stroke (mean [SD] age of 53.25 [19.74] years; 55.63% male) who restarted aspirin use 4 weeks after suffering from TBI and a control group of 60,140 patients with chronic stroke (mean [SD] age of 53.12 [19.22] years; 55.63% male) who discontinued aspirin use after suffering from TBI. The risk of hospitalization of secondary ischemic stroke [adjusted hazard ratio (aHR) 0.694; 95% confidence interval (CI) 0.621-0.756; P < 0.001] and hemorrhagic stroke (aHR 0.642; 95% CI 0.549-0.723; P < 0.001) and all-cause mortality (aHR 0.840; 95% CI 0.720-0.946; P < 0.001) significantly decreased in patients with chronic stroke restarting aspirin use 1 month after suffering from TBI events (including intracranial hemorrhage) in comparison with the control subjects, regardless of those with or without diabetes mellitus, chronic kidney disease, myocardial infarction, atrial fibrillation, clopidogrel use, and dipyridamole use. Restarting aspirin use could lower the risks of secondary stroke (ischemic and hemorrhagic) hospitalization and all-cause mortality in patients with chronic stroke 1 month after suffering from TBI episodes.

Standardized rate of hospitalization for violent injuries among different generations in counties and cities in Taiwan from 2000 to 2015.

This study aimed to understand the distribution of the standardized rate of hospitalization for violent injuries in counties and cities in Taiwan. The ICD-9 diagnosis code N-codes 995.5 (abused child) and 995.8 (abused adult) or E-code E960-E969 (homicide and intentional injury by others) were defined as research cases. The study analyzed the standardized medical treatment rate of children and adolescents aged 0 to 17, adults aged 18 to 64, and older adults over 65 years old suffering from violence for the first time. During the 15-year period, the counties and cities with the highest rate of medical treatment for violent injuries among children (unit: per 105 people) were Pingtung County (33.1 males, 22.9 females), Lienchiang County (8.8 males, 9.8 females), and New Taipei City (8.2 males, 8.8 females). For adults, Pingtung County (73.2 males, 36.8 females), New Taipei City (26.0 males, 14.3 females), and Yunlin County (19.7 males, 7.7 females) registered the highest rates. For older adults, Pingtung County (33.6 persons), New Taipei City (12.5 persons), Yun Lin County (11.2 persons), and Taichung City (9.2 persons) registered the highest rates. The highest rates of older female adults receiving treatment were recorded in Pingtung County (15.1 persons), Yunlin County (9.0 persons), Taichung City (5.5 persons), and New Taipei City (5.1 persons). With the Poisson regression model, the relative risk ratio of seeking medical care owing to violence in Pingtung County (reference: Taipei City) was 25.1 times for children, 20.1 times for adults, and 11.7 times for older adults. The counties and cities with higher rates of violent medical treatment for adults and older adults during the 15-year period were Pingtung County, New Taipei City, and Yunlin County. For children and adolescents, Pingtung County, Lienchiang County, and New Taipei City recorded the highest rates. Pingtung County had the highest risk of sexual violence. These results may be related to the local industrial structure, demographic composition, and other characteristics explained in the text.

Adult abuse and poor prognosis in Taiwan, 2000-2015: a cohort study.

BACKGROUND: To investigate the risk of poor prognosis regarding schizophrenic disorders, psychotic disorders, suicide, self-inflicted injury, and mortality after adult violence from 2000 to 2015 in Taiwan. METHODS: This study used data from National Health Insurance Research Database (NHIRD) on outpatient, emergency, and inpatient visits for two million people enrolled in the National Health Insurance (NHI) from 2000 to 2015. The case study defined ICD-9 diagnosis code N code 995.8 (abused adult) or E code E960-E969 (homicide and intentional injury of another). It analyzed first-time violence in adults aged 18-64 years (study group). 1:4 ratio was matched with injury and non-violent patients (control group). The paired variables were sex, age (± 1 year), pre-exposure to the Charlson comorbidity index, and year of medical treatment. Statistical analysis was conducted using SAS 9.4 and Cox regression for data analysis. RESULTS: In total, 8,726 individuals experienced violence (case group) while34,904 did not experienced violence (control group) over 15 years. The prevalence of poor prognosis among victims of violence was 25.4/104, 31.3/104, 10.5/10,4 and 104.6/104 for schizophrenic disorders, psychotic disorders, suicide or self-inflicted injury and mortality, respectively. Among adults, the risks of suicide or self-inflicted injury, schizophrenic disorders, psychotic disorders, and mortality after exposure to violence (average 9 years) were 6.87-, 5.63-, 4.10-, and 2.50-times (p < 0.01), respectively, compared with those without violence. Among males, the risks were 5.66-, 3.85-, 3.59- and 2.51-times higher, respectively, than those without violence (p < 0.01), and they were 21.93-, 5.57-, 4.60- and 2.46-times higher than those without violence (p < 0.01) among females. CONCLUSION: The risk of poor prognosis regarding schizophrenic disorders, psychotic disorders, suicide, or self-inflicted injury and mortality after adult violence was higher than in those who have not experienced a violent injury. Adults at the highest risk for violent suicide or self-inflicted injuries due to exposure to violent injuries -males were at risk for schizophrenia and females were at risk for suicide or self-inflicted injuries. Therefore, it is necessary for social workers and medical personnel to pay attention to the psychological status of victims of violence.

A High-Fiber Diet or Dietary Supplementation of Acetate Attenuate Hyperoxia-Induced Acute Lung Injury.

A high fiber diet (HFD) and dietary supplementation with acetate have been reported to have beneficial effects in a variety of diseases. We investigated the effects of a HFD and acetate supplementation on the gut microbiota and hyperoxia-induced acute lung injury (HALI) in mice. Mice were fed a control diet, HFD, or acetate supplementation for three weeks, and their gut microbiome composition, lung tissues, and bronchoalveolar lavage fluid (BALF) were examined after exposure to ambient air or hyperoxia. Both the HFD and acetate supplementation modified the gut microbiota community and increased the proportion of acetate-producing bacteria in mice exposed to hyperoxia. The HFD and acetate supplementation also increased the abundance of Bacteroides acidifaciens and reduced gut dysbiosis according to the ratio of Firmicutes to Bacteroidetes. Compared with hyperoxia-exposed mice fed a control diet, both the HFD and acetate supplementation significantly increased the survival time while reducing the severity of pulmonary edema and the concentrations of protein and inflammatory mediators in BALF. Moreover, the HFD and acetate supplementation reduced the production of free radicals, attenuated NF-κB signaling activation, and decreased apoptosis in the lung tissues. Overall, this study indicates that a HFD or acetate supplementation reduces the severity of HALI through alterations in the gut microbiota to exert anti-inflammatory effects.

Cell volume restriction by mercury chloride reduces M1-like inflammatory response of bone marrow-derived macrophages.

Dysregulation of macrophages in the pro-inflammatory (M1) and anti-inflammatory (M2) sub-phenotypes is a crucial element in several inflammation-related diseases and injuries. We investigated the role of aquaporin (AQP) in macrophage polarization using AQP pan-inhibitor mercury chloride (HgCl2). Lipopolysaccharides (LPSs) induced the expression of AQP-1 and AQP-9 which increased the cell size of bone marrow-derived macrophages. The inhibition of AQPs by HgCl2 abolished cell size changes and significantly suppressed M1 polarization. HgCl2 significantly reduced the activation of the nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) pathways and inhibited the production of IL-1ß. HgCl2 attenuated LPS-induced activation of mitochondria and reactive oxygen species production and autophagy was promoted by HgCl2. The increase in the light chain three II/light chain three I ratio and the reduction in PTEN-induced kinase one expression suggests the recycling of damaged mitochondria and the restoration of mitochondrial activity by HgCl2. In summary, the present study demonstrates a possible mechanism of the AQP inhibitor HgCl2 in macrophage M1 polarization through the restriction of cell volume change, suppression of the p38 MAPK/NFκB pathway, and promotion of autophagy.

Obese patients experience more severe OSA than non-obese patients.

To investigate whether previous exposure to obstructive sleep apnea (OSA) increases the risk of obesity in obese and nonobese patients. We identified 24,363 obese patients diagnosed between January 1, 2000, and December 31, 2015, in the Taiwan Longitudinal Health Insurance Database (LHID) 2005 National Health Insurance Research Database; 97,452 sex-, age- and index date-matched nonobese patients were identified from the same database. This study is based on the ninth edition of the International Classification of Sleep Disorders. Multiple logistic regression was used to analyze the previous exposure of obese patients to OSA. P < .05 was considered significant. The average age of 121,815 patients was 44.30 ±â€…15.64 years old; 42.77% were males, and 57.23% were females. Obese patients were more likely to be exposed to OSA than nonobese patients (adjusted odds ratio [AOR] = 2.927, 95% CI = 1.878-4.194, P < .001), and the more recent the exposure period was, the more severely obese the patient, with a dose-response effect (OSA exposure < 1 year, AOR = 3.895; OSA exposure 1 year, <5 years, AOR = 2.933; OSA exposure 5 years, AOR = 2.486). The probability of OSA exposure in obese patients was 2.927 times that in nonobese patients, and the longer the exposure duration was, the more severe the obesity situation, with a dose-response effect (OSA exposure < 1 year, AOR = 2.251; OSA exposure 1 year, <5 years, AOR = 2.986; OSA exposure 5 years, AOR = 3.452). The risk of obesity in subjects with OSA was found to be significantly higher in this nested case-control study; in particular, a longer exposure to OSA was associated with a higher likelihood of obesity, with a dose-response effect.

Bidirectional Relationship Between Tuberculosis and Hypothyroidism: An 18-Year Nationwide Population-Based Longitudinal Cohort Study.

Some antituberculosis agents may cause hypothyroidism, and thyroid hormones play a vital role in Mycobacterium tuberculosis infection. However, the relationship between tuberculosis (TB) and hypothyroidism has not been clearly established. Therefore, this retrospective, longitudinal cohort study aimed to investigate the association between these two diseases using the 2000-2017 data from the Taiwan's National Health Insurance Research Database. The hypothyroidism and TB cohorts were matched with the control group in a 1:4 ratio. Adjusted hazard ratios (aHRs) were assessed using Cox proportional hazards regression analysis in each cohort. In total, 3,976 individuals with hypothyroidism and 35 120 individuals with TB were included in this study. The risk of developing TB in patients with hypothyroidism was 2.91 times higher than that in those without hypothyroidism (95% confidence interval [CI], 1.50-3.65). The subgroup of thyroxine replacement therapy (TRT) had a 2.40 times higher risk (95% CI, 1.26-3.01), whereas the subgroup of non-TRT had a 3.62 times higher risk of developing TB than those without hypothyroidism (95% CI, 2.19-4.84). On the other hand, the risk of developing hypothyroidism in patients with TB was 2.01 times higher than that in those without TB (95% CI, 1.41-2.38). Our findings provide evidence that TB and hypothyroidism are interrelated. Thus, clinicians and public health authorities should monitor the association between these two diseases to reduce the relevant disease burden.

Intermittent Exposure of Hypercapnia Suppresses Allograft Rejection via Induction of Treg Differentiation and Inhibition of Neutrophil Accumulation.

BACKGROUND: In the management of major burn wounds, allogeneic skin transplantation is a critical procedure to improve wound repair. Our previous works found that intermittent exposure to carbon dioxide leads to permissive hypercapnia (HCA) and prolongs skin allograft survival. However, the modulatory effects of HCA exposure on the immune system are not well understood. OBJECTIVES: Our purpose was to investigate how intermittent exposure to HCA can effectively reduce the immune reaction to allogeneic skin graft rejection. METHODS: A fully major histocompatibility complex-incompatible skin transplant from BALB/c to C57BL/6 mice model was utilized. Immune cells from splenic and draining lymph nodes were analyzed by flow cytometry. Serum proinflammatory cytokines were analyzed by ELISA. RESULTS: Serum levels of IFN-γ, IL-2, IL-6, and TNF-α were significantly decreased in the HCA group. Additionally, the percentage of CD8+ cells in draining lymph nodes was significantly lower in HCA than in the control group. Moreover, the generation rate of FoxP3+ regulatory T cells (Tregs) from spleen naïve CD4+ T cells was increased by intermittent exposure to carbon dioxide. The infiltrated neutrophils were also eliminated by HCA. Taken together, we concluded that intermittent hypercapnia exposure could effectively suppress skin rejection by stimulating Treg cell generation and suppressing immune reactions.

Man on Noninvasive Positive Airway Pressure Ventilation With Throat Pain.

Dentures dislodged into throat on bilevel positive airway pressure (BiPAP) ventilation can be overlooked and potentially compromise airway patency. An 81-year-old man with a history of chronic obstructive pulmonary disease (COPD) presented with increased shortness of breath and productive cough for 1 week. Inhaled bronchodilators, parenteral steroids, and BiPAP ventilation were administered for acute exacerbation of COPD complicated with acute hypercapnic respiratory failure. Fifty minutes after receiving BiPAP ventilation, his respiratory condition improved; however, he started to complain of neck pain. The patient remained intolerant to the device 3 hours later, despite receiving assurance that the discomfort might be caused by air pressure through mask ventilation. His throat did not exhibit any abnormality during visual examination. Neck radiographs were subsequently obtained and demonstrated a denture impacted in the hypopharynx. His neck pain resolved after the removal of the dislodged maxillary denture. Denture dislodgement can occur in mask ventilation and compromise airway patency if stuck in the hypopharynx or respiratory tract. Such adverse events may be overlooked on the coexistence of respiratory and pulmonary diseases. A precisely pharyngolaryngeal inspection and complete imaging studies must be performed to facilitate early identification and further retrieval intervention.

Methods of Weaning From Mechanical Ventilation in Adult: A Network Meta-Analysis.

Background/Objective: The aim of study is to assess the efficacy of each ventilator weaning method for ventilated patients in intensive care units (ICUs). Methods: A systematic search was conducted using PubMed, Embase, and China National Knowledge Infrastructure to identify randomized control studies on ventilated patients regarding extubation associated outcomes (weaning success or failure, proportion requiring re-intubation, or mortality) from inception until April 01, 2020. Commonly used ventilation modes involved pressure support ventilation, synchronized intermittent mandatory ventilation, automatic tube compensation, continuous positive airway pressure, adaptive support ventilation, neurally adjusted ventilatory assist, proportional assisted ventilation, and SmartCare. Pooled estimates regarding extubation associated outcomes were calculated using network meta-analysis. Results: Thirty-nine randomized controlled trials including 5,953 patients met inclusion criteria. SmartCare and proportional assist ventilation were found to be effective methods in increasing weaning success (odds ratio, 2.72, 95% confidence interval (CI), 1.33-5.58, P-score: 0.84; odds ratio, 2.56, 95% CI, 1.60-4.11, P-score: 0.83; respectively). Besides, proportional assist ventilation had superior in reducing proportion requiring re-intubation rate (odds ratio, 0.48, 95% CI, 0.25-0.92, P-score: 0.89) and mortality (odds ratio, 0.48, 95% CI, 0.26-0.92, P-score: 0.91) than others. Conclusion: In general consideration, our study provided evidence that weaning with proportional assist ventilation has a high probability of being the most effective ventilation mode for patients with mechanical ventilation regarding a higher rate of weaning success, a lower proportion requiring reintubation, and a lower mortality rate than other ventilation modes.

Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury.

Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury.

Obesity Attenuates Ventilator-Induced Lung Injury by Modulating the STAT3-SOCS3 Pathway.

Background: Ventilator-induced lung injury (VILI) is characterized by vascular barrier dysfunction and suppression of alveolar fluid clearance (AFC). Obesity itself leads to chronic inflammation, which may initiate an injurious cascade to the lungs and simultaneously induce a protective feedback. In this study, we investigated the protective mechanism of obesity on VILI in a mouse model. Methods: The VILI model was set up via 6-h mechanical ventilation with a high tidal volume. Parameters including lung injury score, STAT3/NFκB pathway, and AFC were assessed. Mice with diet-induced obesity were obtained by allowing free access to a high-fat diet since the age of 3 weeks. After a 9-week diet intervention, these mice were sacrificed at the age of 12 weeks. The manipulation of SOCS3 protein was achieved by siRNA knockdown and pharmaceutical stimulation using hesperetin. WNK4 knockin and knockout obese mice were used to clarify the pathway of AFC modulation. Results: Obesity itself attenuated VILI. Knockdown of SOCS3 in obese mice offset the protection against VILI afforded by obesity. Hesperetin stimulated SOCS3 upregulation in nonobese mice and provided protection against VILI. In obese mice, the WNK4 axis was upregulated at the baseline, but was significantly attenuated after VILI compared with nonobese mice. At the baseline, the manipulation of SOCS3 by siRNA and hesperetin also led to the corresponding alteration of WNK4, albeit to a lesser extent. After VILI, WNK4 expression correlated with STAT3/NFκB activation, regardless of SOCS3 status. Obese mice carrying WNK4 knockout had VILI with a severity similar to that of wild-type obese mice. The severity of VILI in WNK4-knockin obese mice was counteracted by obesity, similar to that of wild-type nonobese mice only. Conclusions: Obesity protects lungs from VILI by upregulating SOCS3, thus suppressing the STAT3/NFκB inflammatory pathway and enhancing WNK4-related AFC. However, WNK4 activation is mainly from direct NFκB downstreaming, and less from SOCS3 upregulation. Moreover, JAK2-STAT3/NFκB signaling predominates the pathogenesis of VILI. Nevertheless, the interaction between SOCS3 and WNK4 in modulating VILI in obesity warrants further investigation.

Poloxamer 188 Attenuates Ischemia-Reperfusion-Induced Lung Injury by Maintaining Cell Membrane Integrity and Inhibiting Multiple Signaling Pathways.

Background: Poloxamer 188 (P188) possesses anti-inflammatory properties and can help to maintain plasma membrane function. P188 has been reported to exert beneficial effects in the treatment of various disorders. However, the effects of P188 in ischemia/reperfusion (IR)-induced acute lung injury have not been examined. Methods: We investigated the ability of P188 to attenuate IR-induced acute lung injury in rats and hypoxia/reoxygenation (HR) injury in murine epithelial cells. Isolated perfused rat lungs were exposed to 40 min ischemia followed by 60 min reperfusion to induce IR injury. Results: IR led to lung edema, increased pulmonary arterial pressure, promoted lung tissue inflammation and oxidative stress, and upregulated the levels of TNF-α, IL-6 and CINC-1, and increased Lactic dehydrogenase (LDH) activity in bronchoalveolar lavage fluid. IR also downregulated the levels of inhibitor of κB (IκB-α), upregulated nuclear factor (NF)-κB (NF-κB), and promoted apoptosis in lung tissues. P188 significantly suppressed all these effects. In vitro, P188 also exerted a similar effect in murine lung epithelial cells exposed to HR. Furthermore, P188 reduced the number of propidium iodide-positive cells, maintained cell membrane integrity, and enhanced cell membrane repair following HR. Conclusion: We conclude that P188 protects against lung IR injury by suppressing multiple signaling pathways and maintaining cell membrane integrity.

Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression.

Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.

Black Carbon Content in Airway Macrophages is Associated with Reduced CD80 Expression and Increased Exacerbations in Former Smokers With COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by recurrent exacerbations. Macrophages play a critical role in immune response and tissue repair in COPD. Airway macrophages (AM) are exposed to environmental exposures which are retained in the cytoplasmic material. Both biomass and particulate matter have been linked to higher AM black carbon. It is unknown if AM black carbon is associated with COPD morbidity and macrophage phenotype. METHODS: Former smokers with COPD were enrolled and sputum induction was performed to obtain airway macrophages. Macrophages underwent black carbon quantification and flow cytometry phenotyping. Health information was obtained the same day as sputum induction and prospective exacerbations were assessed by monthly telephone calls. RESULTS: We studied 30 former smokers with COPD who had a mean age of 67 years and mean forced expiratory volume in 1 second (FEV1)% predicted of 60.8%. Higher AM black carbon content was associated with increased total exacerbations and severe exacerbations and reduced CD80 expression. CONCLUSION: AM black carbon association with respiratory morbidity is largely unexplored and this is the first study to identify association with prospective exacerbations. Macrophages expressed reduced CD80, a surface marker providing costimulatory signals required for development of antigen-specific immune responses. Our findings suggest that reduced CD80 expression is the pathophysiologic mechanism for the association of AM black carbon content and increased exacerbations. Therefore, beyond solely serving as a marker for increased exposures, AM black carbon content may be a predictor of future exacerbations given a macrophage less equipped to respond to an acute infectious exposure.