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.

Association between surgical repair of aortic aneurysms and the diagnosis of intracranial aneurysms.

OBJECTIVE: Aortic aneurysms (AAs) and intracranial aneurysms (IAs) share several clinical risk factors, a genetic predisposition, and molecular signaling pathways. Nonetheless, associations between IAs and AAs remain to be thoroughly validated in large-scale studies. In addition, no effective medical therapies exist for unruptured IAs or AAs. METHODS: Data for this nationwide, population-based, retrospective, cohort study described herein were obtained from the National Health Insurance Research Database in Taiwan. The study outcomes assessed were (1) the cumulative incidence of IAs, which was compared between AA and patients without an AA and (2) the cumulative incidence of IAs in patients with AAs during the 13-year follow-up period, which was further compared among those who underwent open surgical repair (OSR), endovascular aneurysm repair or nonsurgical treatment (NST). RESULTS: Our analyses included 20,280 patients with an AA and 20,280 propensity score-matched patients without an AA. Compared with the patients without an AA, patients with AA exhibited a significantly increased risk of an IA diagnosis (adjusted hazard ratio [HR], 3.395; P < .001). Furthermore, 6308 patients with AAs were treated with surgical intervention and another 6308 propensity score-matched patients with AAs were not. Patients with an AA who underwent OSR had a significantly lower risk of being diagnosed with an IA than patients with an AA who underwent endovascular aneurysm repair or NST (adjusted HR, 0.491 [P < .001] and adjusted HR, 0.473 [P < .001], respectively). CONCLUSIONS: We demonstrated an association between IAs and AAs, even after adjusting for several comorbidities. We also found that OSR was associated with fewer recognized IAs than NST.

Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production.

BACKGROUND: It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection. METHODS: VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated. RESULTS: Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody. CONCLUSIONS: Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production.

Obstructive Sleep Apnoea and Aortic Aneurysm: A Nationwide Population-Based Retrospective Study.

OBJECTIVE: To determine whether patients with obstructive sleep apnoea (OSA) have an increased risk of aortic aneurysm (AA). METHODS: The data for the nationwide population-based retrospective cohort study described here were obtained from the Taiwan National Health Insurance Research Database (NHIRD). We selected adult patients who had been newly diagnosed as having OSA and were followed up between 2000 and 2010. We excluded patients who had been diagnosed as having AA before the date of the new OSA diagnosis. The control cohort consisted of individuals who had no OSA history. The patients and the control cohort were selected by 1: 4 matching according to the following baseline variables: sex, age, index year, and comorbidities. The outcome measure was AA diagnosis. RESULTS: In total, 31,274 patients diagnosed as having OSA were identified. Compared to patients without OSA, they had no significantly discrepant cumulative risk of developing AA in subsequent years (p from log-rank test = 0.442). We used the Cox proportional-hazards regression model, which found that only male sex, older age, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and coronary artery disease were independently associated with AA occurrence among subjects with an OSA diagnosis. OSA was not associated with AA development. On the other hand, in the subgroup of COPD, patients with OSA had a higher incidence of risk of AA than those without OSA. CONCLUSION: When compared to those without OSA, patients with OSA do not have an increased AA risk.

Association between Atrial Fibrillation and Aortic Aneurysms: A Population-Based Cohort Study.

OBJECTIVE: Atrial fibrillation (AF) is the most common form of sustained arrhythmia. Several molecular pathways associated with the pathogenesis of AF also participate in the initiation and progression of aortic aneurysm (AA). In this study, we aimed to evaluate potential associations between AA and AF. PATIENTS AND METHODS: The data for this nationwide population-based retrospective cohort study were obtained from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each case and the controls were categorized using the 9th revision of the International Classification of Diseases (ICD-9). Odds ratios and 95% confidence intervals for associations between AF and AA were estimated using Cox regression and adjusted for comorbidities. RESULTS: Our analyses included 116,225 AF cases and 116,225 propensity score-matched controls. Compared with the controls, the patients with AF exhibited a significantly increased risk of developing an AA (adjusted hazard ratio, HR 1.243, p < 0.001). Another cohort of 19,776 patients diagnosed with AA were identified, and 19,776 propensity score-matched patients were included as controls. Patients who had AA were also at an increased risk of developing AF (adjusted HR 1.187, p < 0.001). Heart failure (HF) was a common risk factor for both AA and AF. CONCLUSION: There are associations between AF and AA. HF is a mutual risk factor for the development of AF and AA.

Fucoidan attenuates angiotensin II-induced abdominal aortic aneurysms through the inhibition of c-Jun N-terminal kinase and nuclear factor κB activation.

BACKGROUND: Rupture of abdominal aortic aneurysm (AAA) is one of the leading causes of sudden death among the elderly. Most incidental AAAs are below the threshold for intervention at the time of detection; however, there is no evidence that commonly used cardiovascular drugs have clinical beneficial effects on AAA progression. Therefore, in addition to current cardiovascular risk-reducing treatments, an adjunctive medical therapy targeting the regulation of extracellular matrix metabolism is still required in the clinical setting. Fucoidan is an extract of brown seaweed and a sulfated polysaccharide. Emerging evidence suggests that fucoidan has potential cardiovascular applications. Numerous investigations of fucoidan in diseases of the cardiovascular system have mainly focused on its pleiotropic anti-inflammatory effects. Specifically, fucoidan has been shown to have matrix metalloproteinase (MMP)-reducing effects in several studies. We aimed to evaluate the beneficial effect of fucoidan on aneurysmal growth in a murine model of aortic aneurysm and further provide a rationale for using fucoidan as a medical adjunctive therapy. METHODS: A murine model of angiotensin II (Ang II)-induced AAA was used to assess the therapeutic effects of fucoidan on AAA growth in vivo. The characteristics and quantification of AAAs were determined in situ. Human umbilical vein endothelial cells were used for studying the involved pathways in vitro. Western blotting was used to detect the involved signaling pathways both in vivo and in vitro. RESULTS: Treatment with fucoidan significantly reduced the incidence of AAA formation. Administration of fucoidan significantly attenuated Ang II-induced aortic expansion from 1.56 ± 0.76 mm to 1.09 ± 0.30 mm. Administration of fucoidan significantly suppressed MMP-2 and MMP-9 activities and reduced the grade of elastin degradation in vivo. In vitro, we found that fucoidan could ameliorate the Ang II-induced phosphorylation of c-Jun N-terminal kinase and nuclear factor κB p65, and it further reduced MMP and reactive oxygen species production. CONCLUSIONS: Fucoidan inhibits the progression of experimental AAA growth through the attenuation of proinflammatory nuclear factor κB and c-Jun N-terminal kinase activation. Fucoidan could be a potential medical adjunctive therapy for small AAAs.

Kinect-based real-time audiovisual feedback device improves CPR quality of lower-body-weight rescuers.

BACKGROUND: Chest compression (CC) quality is associated with rescuer posture and body weight. We designed a Kinect module-based real-time audiovisual feedback (AVF) device to investigate the relationship between rescuer posture, body weight, and CC quality. METHODS: A total of 100 healthcare professionals were enrolled as participants in this randomized trial. A Kinect-based sensor system was used to monitor the depth and rate of CC and provide further real-time feedback. All participants were asked to perform continuous CC on a manikin with and without feedback for 2min individually in either a kneeling or standing position. RESULTS: A kneeling posture can provide higher rate of CC than a standing posture can (111.4±22.6 per minute vs. 99.1±18.9per minute, p value=0.005). Real-time AVF feedback can provide a better compression depth, rate, and effective compression ratio (6.16±1.88cm vs. 5.54±1.89cm, p value=0.02; 103.2±21.0/min vs. 96.7±25.8/min, p value=0.03; 62.6±28.0% vs. 51.0±33.2%, p value=0.004). Regardless of the effect of real-time feedback, the CC depth correlated to the rescuers' body weight. Rescuers who weighed below 71kg benefited from the Kinect module-based real-time AVF device in terms of improved CC quality. CONCLUSION: The Kinect-based AVF device can significantly improve CC quality in manikin training in rescuers with their body weight<71kg.

Correction: Wen-I Liao, et al. Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury. Int. J. Mol. Sci. 2017, 18, 1771.

The authors would like to make a correction to their published paper [1][...].

Targeting of nicotinamide phosphoribosyltransferase enzymatic activity ameliorates lung damage induced by ischemia/reperfusion in rats.

BACKGROUND: Emerging evidence reveals that nicotinamide phosphoribosyltransferase (NAMPT) has a significant role in the pathophysiology of the inflammatory process. NAMPT inhibition has a beneficial effect in the treatment of a variety of inflammatory diseases. However, it remains unclear whether NAMPT inhibition has an impact on ischemia-reperfusion (I/R)-induced acute lung injury. In this study, we examined whether NAMPT inhibition provided protection against I/R lung injury in rats. METHODS: Isolated perfused rat lungs were subjected to 40 min of ischemia followed by 60 min of reperfusion. The rats were randomly allotted to the control, control + FK866 (NAMPT inhibitor, 10 mg/kg), I/R, or I/R + FK866 groups (n = 6 per group). The effects of FK866 on human alveolar epithelial cells exposed to hypoxia-reoxygenation (H/R) were also investigated. RESULTS: Treatment with FK866 significantly attenuated the increases in lung edema, pulmonary arterial pressure, lung injury scores, and TNF-α, CINC-1, and IL-6 concentrations in bronchoalveolar lavage fluid in the I/R group. Malondialdehyde levels, carbonyl contents and MPO-positive cells in lung tissue were also significantly reduced by FK866. Additionally, FK866 mitigated I/R-stimulated degradation of IκB-α, nuclear translocation of NF-κB, Akt phosphorylation, activation of mitogen-activated protein kinase, and downregulated MKP-1 activity in the injured lung tissue. Furthermore, FK866 increased Bcl-2 and decreased caspase-3 activity in the I/R rat lungs. Comparably, the in vitro experiments showed that FK866 also inhibited IL-8 production and NF-κB activation in human alveolar epithelial cells exposed to H/R. CONCLUSIONS: Our findings suggest that NAMPT inhibition may be a novel therapeutic approach for I/R-induced lung injury. The protective effects involve the suppression of multiple signal pathways.

Usefulness of glycated hemoglobin A1c-based adjusted glycemic variables in diabetic patients presenting with acute ischemic stroke.

Acute hyperglycemia is a common condition among patients with diabetes who are admitted to the emergency department (ED) for acute ischemic stroke (AIS). Previous findings regarding the association between hyperglycemia at admission and adverse outcomes among patients with diabetes and AIS have been inconsistent. When investigating this association, it is necessary to consider premorbid blood glucose control. The objective of the current study was to assess whether HbA1c-based adjusted glycemic variables were associated with unfavorable outcomes among patients admitted to the hospital for AIS. We retrospectively analyzed data from 309 patients who were hospitalized for AIS at a single medical center in Taiwan between January 1, 2013, and October 31, 2015. We found that 1) HbA1c-based adjusted glycemic variables, including the glycemic gap and stress hyperglycemia ratio, were associated with both AIS severity and neurological status at discharge; additionally, 2) HbA1c-based adjusted glycemic variables showed superior discriminative power compared with acute hyperglycemia regarding the development of severe AIS. We conclude that both the glycemic gap and stress hyperglycemia ratio might be useful in assessing the disease severity and prognosis of patients presenting with AIS. Further prospective long-term follow-up studies should be performed to validate these findings.

Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury.

Annexin A1 (AnxA1) is an endogenous protein that modulates anti-inflammatory processes, and its therapeutic potential has been reported in a range of inflammatory diseases. The effect of AnxA1 on ischemia-reperfusion (IR)-induced lung injury has not been examined. In this study, isolated, perfused rat lungs were subjected to IR lung injury induced by ischemia for 40 min, followed by reperfusion for 60 min. The rat lungs were randomly treated with vehicle (phosphate-buffered saline), and Ac2-26 (an active N-terminal peptide of AnxA1) with or without an N-formyl peptide receptor (FPR) antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2). An in vitro study of the effects of Ac2-26 on human alveolar epithelial cells subjected to hypoxia-reoxygenation was also investigated. Administration of Ac2-26 in IR lung injury produced a significant attenuation of lung edema, pro-inflammatory cytokine production recovered in bronchoalveolar lavage fluid, oxidative stress, apoptosis, neutrophil infiltration, and lung tissue injury. Ac2-26 also decreased AnxA1 protein expression, inhibited the activation of nuclear factor-κB and mitogen-activated protein kinase pathways in the injured lung tissue. Finally, treatment with Boc2 abolished the protective action of Ac2-26. The results indicated that Ac2-26 had a protective effect against acute lung injury induced by IR, which may be via the activation of the FPR.

Paraplegia caused by aortic coarctation complicated with spinal epidural hemorrhage.

Aortic coarctation complicated with spinal artery aneurysm rupture is exceptionally rare and can be source of intraspinal hemorrhage with markedly poor prognosis. A 21-year-old man visited the emergency department because of chest and back pain along with immobility of bilateral lower limbs immediately after he woke up in the morning. Complete flaccid paraplegia and hypoesthesia in dermatome below bilateral T3 level and pain over axial region from neck to lumbar region were noted. A computed tomography excluded aortic dissection. Magnetic resonance imaging revealed a fusiform lesion involving the anterior epidural space from C7 to T2 level suspected of epidural hemorrhage, causing compression of spinal cord. He started intravenous corticosteroid but refused operation concerning the surgical benefits. Severe chest pain occurred with newly onset right bundle branch block that developed the other day. Coronary artery angiography revealed myocardial bridge of left anterior descending coronary artery at middle third and coarctation of aorta. He underwent thoracic endovascular aortic repair uneventfully. The patient was hemodynamically stable but with slow improvement in neurologic recovery of lower limbs. Aortic coarcation can cause paralysis by ruptured vascular aneurysms with spinal hemorrhage and chest pain that mimics acute aortic dissection. A history of hypertension at young age and aortic regurgitated murmurs may serve as clues for further diagnostic studies. Cautious and prudent evaluation and cross disciplines cares are essential for diagnosis and successful management of the disease.

The physiological effects and quality of chest compressions during CPR at sea level and high altitude.

BACKGROUND: Rescuers that undergo acute ascent without acclimatization can experience acute mountain sickness. Although performing cardiopulmonary resuscitation (CPR) for a short period requires intensive effort at sea level, performing CPR at high altitude is even more exhausting and can endanger the rescuer. Therefore, we conducted a pilot study to compare the quality of resuscitation in health professionals at high altitude (3100 m) and that at sea level. METHODS: Thirty-eight participants were asked to performed continuous chest compression CPR (CCC-CPR) for 5 minutes at sea level and at high altitude. Cardiopulmonary resuscitation recording technology was used to objectively quantify the quality of the chest compressions (CCs), including the depth and rate thereof. RESULTS: At high altitude, rescuers showed a statistically significant decrease in blood oxygen saturation and an increase in systolic blood pressure, diastolic blood pressure, heart rate, and fatigue, as measured with the Borg score, after CCC-CPR compared with resting levels. The analysis of the time-dependent deterioration in the quality of CCC-CPR showed that the depth of CCs declined from the mean depth of the first 30 seconds after CCC-CPR to that at more than 120 seconds after CCC-CPR at both sea level and high altitude. The average number of effective CCs declined after CCC-CPR was performed for 1 minute at sea level and high altitude. CONCLUSIONS: The quality of CC rapidly declined at high altitude. At high altitude, the average number of effective CC decreases; and this decrease became significant after continuous CCs had been performed for 1 minute.

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.

Hyperacute cerebral fat embolism in a patient with femoral shaft fracture.

Fat embolism syndrome is a potentially fatal complication and occurs most commonly after long bone fracture. In patients who sustained severe trauma, both cerebral fat embolism(CFE) and diffuse axonal injury (DAI) could be the cause of altered consciousness in the absence of marked intracranial lesions in cranial computed tomography. However, distinguishing CFE and DAI can be difficult clinically. Generally, DAI develops immediately after the insult, whereas CFE occurs 48 to 72 hours after the trauma and even after internal fixation for the fractures. Fat embolism syndrome develops within an average of 48.5 hours after long bone fracture [1] but has never been reported to occur in less than 2 hours. Here, we present a patient who developed hyperacute CFE and eventually had poor neurological outcome, in contrast to previous reports stating that CFE usually has a long latent period and favorable outcomes.

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.

Regulation of Lung Immune Tone by the Gut-Lung Axis via Dietary Fiber, Gut Microbiota, and Short-Chain Fatty Acids.

Lung immune tone, i.e. the immune state of the lung, can vary between individuals and over a single individual's lifetime, and its basis and regulation in the context of inflammatory responses to injury is poorly understood. The gut microbiome, through the gut-lung axis, can influence lung injury outcomes but how the diet and microbiota affect lung immune tone is also unclear. We hypothesized that lung immune tone would be influenced by the presence of fiber-fermenting short-chain fatty acid (SCFA)-producing gut bacteria. To test this hypothesis, we conducted a fiber diet intervention study followed by lung injury in mice and profiled gut microbiota using 16S sequencing, metabolomics, and lung immune tone. We also studied germ-free mice to evaluate lung immune tone in the absence of microbiota and performed in vitro mechanistic studies on immune tone and metabolic programming of alveolar macrophages exposed to the SCFA propionate (C3). Mice on high-fiber diet were protected from sterile lung injury compared to mice on a fiber-free diet. This protection strongly correlated with lower lung immune tone, elevated propionate levels and enrichment of specific fecal microbiota taxa; conversely, lower levels of SCFAs and an increase in other fatty acid metabolites and bacterial taxa correlated with increased lung immune tone and increased lung injury in the fiber-free group. In vitro , C3 reduced lung alveolar macrophage immune tone (through suppression of IL-1ß and IL-18) and metabolically reprogrammed them (switching from glycolysis to oxidative phosphorylation after LPS challenge). Overall, our findings reveal that the gut-lung axis, through dietary fiber intake and enrichment of SCFA-producing gut bacteria, can regulate innate lung immune tone via IL-1ß and IL-18 pathways. These results provide a rationale for the therapeutic development of dietary interventions to preserve or enhance specific aspects of host lung immunity.

Acetate, a gut bacterial product, ameliorates ischemia-reperfusion induced acute lung injury in rats.

Recent data suggest that short-chain fatty acids (SCFAs), the major fermentation product from gut microbial degradation of dietary fiber, have protective effects against renal ischemia-reperfusion (IR) injury, colitis, and allergic asthma. However, the effect of SCFAs on acute lung injury (ALI) caused by IR is still unclear. In this study, we examine whether SCFAs have protective effects against IR-induced ALI and explore possible protective mechanisms. IR-induced ALI was established by 40 min ischemia followed by 60 min reperfusion in isolated perfused rat lungs. Rats were randomly assigned to one of six groups: control, control + acetate (400 mg/kg), IR, and IR + acetate at one of three dosages (100, 200, 400 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed at the end of the experiment. In vitro, mouse lung epithelial cells (MLE-12) subjected to hypoxia-reoxygenation (HR) were pretreated with acetate (25 mmol/L) and GPR41 or GPR43 siRNA. Acetate decreased lung weight gain, lung weight/body weight ratios, wet/dry weight ratios, pulmonary artery pressure, and protein concentration of the BALF in a dose-dependent manner for IR-induced ALI. Acetate also significantly inhibited the production of TNF-α, IL-6 and CINC-1 in the BALF. Moreover, acetate treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, acetate mitigated IR-induced apoptosis and tight junction disruption in injured lung tissue. In vitro analyses showed that acetate attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR. The protective effects of acetate in vitro were significantly abrogated by GPR41 or GPR43 siRNA. Acetate ameliorates IR-induced acute lung inflammation and its protective mechanism appears to be via the GPR41/43 signaling pathway. Based on our findings, acetate may provide a novel adjuvant therapeutic approach for IR-induced lung injury.