Lung Injury Score Research Articles

337.3: Effects of Tacrolimus on Mechanical and Humoral Determinants of Brain Death-Induced Lung Injury

Background: Donor brain death-induced lung injury may compromise graft function after transplantation. The mechanisms of this particular form of neurogenic lung edema and its possible prevention by immunomodulator Tacrolimus remain incompletely understood. Methods and Results: Brain death was induced, by slow intracranial infusion of blood, in anesthetized pigs after randomisation to placebo (n=9) or to Tacrolimus (n=8). One, three, five and seven hours after brain death, pulmonary artery pressure (Pap), wedged Pap (Papo), right atrial pressure (Pra), effective pulmonary capillary pressure (Pcap), systemic artery pressure (Psa) and thermodilution cardiac output (Q) were measured. Blood and lung tissue were sampled and lung injury scored on pathological examination. Brain death was associated with marked increases in Pap, PVR and Pcap, decreases in Psa and Q with growing need for Noradrenaline while Ppao and Pra remained in a physiological range. Arterial O2 pressure to fraction of inspired O2(PaO2/FiO2) decreased. Brain death was associated with increased lung injury score together with increased gene expressions of interleukin (IL)-6 and IL-1b, heme-oxygenase-1, signal transducer and activator of transcription-3. Lung tissue pro-inflammatory IL-6/IL-10 ratio was decreased and pro-apoptotic Bax/Bcl2 ratio was increased. Tacrolimus partially corrected pulmonary hypertension and lung tissue biological perturbations. PaO2/FiO2 was inversely correlated to PCP and lung injury score. Serum IL-6 and IL-1b were correlated to PCP. Conclusion: Brain death induced lung injury is related to effective pulmonary capillary hypertension with normal PAWP and pro-inflammatory and pro-apoptotic biological changes all partially reversed by preventive Tacrolimus treatment.

315.5: Mesenchymal Stromal Cell Therapy as Promising Option To Increase Organ Availability and Reduce Graft Failure

Introduction: Lung transplantation (LTx) is an established therapeutic option for end-stage pulmonary disease. However, waiting lists are long and the treatments remains hampered by donor lung scarcity accompanied with high early and late mortality rates. Novel treatment options to regenerate marginal donor lungs turned down for transplant are needed to combat both waiting list mortality and post-operative complications such as primary graft dysfunction (PGD). Although donor numbers increase, donor organ utility is low due to acute lung injury (ALI) which can be induced by gastric aspiration. Mesenchymal stromal cells (MSCs) have caught attention for organ regeneration as they display an array of potentially beneficial effects: they are known to be immunomodulatory, antifibrotic and microbiocidal. MSCs have demonstrated tissue regenerative capacities as documented in preclinical studies, e.g., improved function of diseased lungs. Aim: The aim of the current study is to evaluate the effect of MSCs administered to aspiration damaged lungs during ex vivo lung perfusion (EVLP) and to recipients post transplantation with a focus on their capacity to improve damaged lungs and to decrease the incidence of PGD at 72h post transplantation. Materials and Methods: Lung injury was induced in 12 donor pigs using gastric content with a pH of 2. The donor-recipient pairs were randomized to receive MSCs or placebo treatment during the beginning of EVLP and post LTx. Lungs were treated with EVLP for 4 hours followed by a left lung transplantation. The recipient was kept under anesthesia and closely monitored for three days post LTx. In the final phase of the experimental setup an isolated assessment of the transplanted lung was achieved following a right pneumonectomy. Treatment effects were assessed by clinically relevant parameters, including PaO2/FiO2 ratio, pulmonary vascular resistance (PVR), and lactate, further by histopathological changes, immune cell counts in peripheral blood and cytokine and chemokine levels in plasma and bronchoalveolar lavage fluid during the course of the experiment. Results: The lung functionality as evaluated by the PaO2/FiO2 ratios showed significantly increased lung function in treated recipients compared to both the non-treated recipients and to all lungs at the time of confirmed ALI. A tendency of higher PVR was seen among the non-treated recipients however, not significantly. Lactate was unchanged in both groups. Lung injury scores were also reduced in the treated group as compared to the non-treated group and to the lungs after lung injury was induced. On the third day of follow-up of the recipients, all recipients in the treatment group had PGD grade 0, while the non-treated group consisted of one recipient with grade 0, three with grade 2 and two with grade 3. Conclusion: MSC treatment emerges as a promising therapeutic option for restoring injured donor lungs for reacceptance into the donor pool and decreasing the incidence of PGD.

Electroacupuncture pretreatment protects septic rats from acute lung injury by relieving inflammation and regulating macrophage polarization.

Macrophage polarization toward the M2 phenotype may attenuate inflammation and have a therapeutic effect in acute lung injury (ALI). To investigate the role of electroacupuncture (EA) pretreatment on the inflammatory response and macrophage polarization in a septic rat model of lipopolysaccharide (LPS)-induced ALI. Male Sprague Dawley rats (n = 24) were randomly divided into three groups (n = 8 each): control (Ctrl), ALI (LPS) and pre-EA (LPS + EA pretreatment). ALI and pre-EA rats were injected with LPS via the caudal vein. Pulmonary edema was assessed by left upper pulmonary lobe wet-to-dry (W/D) ratios. Lung injury scores were obtained from paraffin-embedded and hematoxylin and eosin-stained sections of the left lower pulmonary lobe. Inflammatory activation was quantified using serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β, transforming growth factor (TGF)-β and IL-10 levels measured by enzyme linked immunosorbent assay (ELISA). Macrophage phenotype was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Mean lung W/D ratio was significantly lower and serum IL-1β levels were decreased in pre-EA rats compared to ALI rats (P < 0.05). TNF-α mRNA expression was decreased and mannose receptor (MR) and Arg1 mRNA expression was increased in the lung tissues of pre-EA rats compared to ALI rats (P < 0.01). Arg1 protein expression was similarly increased in the lung tissues of pre-EA rats compared to ALI rats (P < 0.05). EA pretreatment may play a protective role by promoting macrophage polarization to the M2 phenotype in a septic rat model of LPS-induced ALI.

The Renshen Chishao Decoction Could Ameliorate the Acute Lung Injury but Could Not Reduce the Neutrophil Extracellular Traps Formation.

The acute lung injury (ALI) causes severe pulmonary diseases, leading to a high mortality rate. The Renshen and Chishao have protective and anti-inflammatory effects against the ALI. To explore the protective effects of the Renshen Chishao (RC) decoction against the ALI, we established the lipopolysaccharide-indued ALI model and randomly divided the mice into seven groups: control group, ALI group, high-dose RC group, middle-dose RC group, low-dose RC group, middle-dose RC group + CXCR2 antagonist group, and ALI + CXCR2 antagonist group. We estimated the lung injury by the hematoxylin and eosin staining, the neutrophil extracellular traps (NETs) formations by the immunofluorescence colocalization and enzyme-linked immunosorbent assay (ELISA), and the CXCR2/CXCL2 pathway by the flow cytometry, ELISA, and real-time polymerase chain reaction. We conducted the high-throughput sequencing and enrichment analyses to explore the potential mechanisms. The results showed that the RC decoction pathologically ameliorated the lipopolysaccharide-induced lung injury and inflammatory response but failed to reduce the circulating and lung tissue NETs formation and the blood neutrophil percent. The high-dose RC decoction increased the plasma CXCL2 level, but the RC decoction had no effects on the neutrophilic CXCR2 levels. Under the inhibition of the CXCR2, the middle-dose RC decoction still decreased the lung injury score but as yet had unobvious influence on the NETs formation. Other potential mechanisms of the RC decoction against the ALI involved the pathways of ribosome and coronavirus disease 2019 (COVID-19); the target genes of inflammatory factors, such as Ccl17, Cxcl17, Cd163, Cxcr5, and Il31ra, and lncRNAs; and the regulations of the respiratory cilia. In conclusion, the RC decoction pathologically ameliorated the lipopolysaccharide-induced lung inflammatory injury via upregulating the CXCL2/CXCR2 pathway but could not reduce the circulating or lung tissue NETs formation.

Assessment of the Effects of Quercetin on Lung Injury After Hind Limb Ischemia Reperfusion in Rats

Background: Quercetin has antioxidant and anti-inflammatory effects. Although there are previous animal experi-ments investigating Quercetin’s effect on ischemia reperfusion (IR) injury in the literature, studies involving effect of lower extremity IR on remote organ are rare.Materials and Methods: 18 male Wistar Albino rats were randomly divided into 3 groups, 6 in each group as; Cont-rol (C), Ischemia-reperfusion (IR), IR-Quercetin, (IR-Q). Their weights were between 200-250 g. 30 minutes before the procedure20 mg/kgQuercetin was administered via intraperitoneal route. In the IR groups, infrarenal abdomi-nal aorta was clamped by an atraumatic microvascular clamp. After 120 minutes of ischemia and reperfusion was achieved for another 120 minutes. When reperfusion period ended, tissue samples were taken from the lungs. Malondialdehyde (MDA) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activity and histopathological parameters were compared.Results: We found the MDA level in the IR group higher than the control group (p&amp;lt;0.0001). Lower MDA level was found in the IR-Q group compared tothe IR group (p=0.012). SOD and CAT enzyme activity in the IR group was notably lower in the control group (p&amp;lt;0.0001, p&amp;lt;0.001, respectively). Higher SOD and CAT enzyme activities were found in the IR-Q group compared to the IR group (p=0.012, p&amp;lt;0.001, respectively). Neutrophil infiltra-tion/aggregation, alveolar wall thickness and total lung injury score were notably higher in IR group than in C group (p=0.001, p=0.002, p&amp;lt;0.0001, respectively). In addition, a statistically significant decrease was observed in the Quercetin treated group in neutrophil infiltration/aggregation, alveolar wall thickness and total lung injury score compared to the IR group (p=0.023, p=0.022, p=0.002, respectively).Conclusions: We determined that intraperitoneally administered Quercetin at a dose of 20 mg/kg30 minutes before ischemia in rats reduces lipid peroxidation, oxidative stress and reduces the damage caused by IR in lung histo-pathology.Study findings suggest that Quercetin has a lung protective effect when administered before IR.

The oncogene ABL1 regulates the inflammatory response of innate immunity via mediating TRAF6 ubiquitination

The oncogene ABL1 plays an important role in various cancers, while its roles remain unclear in pneumonia. This study aims to investigate the roles of ABL1 in pneumonia and the underlying mechanisms. RNA sequencing was used to determine the expressions of multiple kinases in the PBMCs. A series of overexpression and knockout cell lines were constructed. Besides, an intranasal lung infection mouse model was pre-treated with asciminb. ELISAs and qPCR were used to determine the levels of target genes. In addition, STRING Interaction Network and Immunoblotting assays were used to determine the interaction between target proteins. An elevation in ABL1 was observed in the infant with Ecoli pneumonia. ABL1 was positively correlated to the levels of inflammatory cytokines and the activation of the NF-kB pathways. In vivo data demonstrated that the inhibition of ABL1 suppressed the inflammatory cytokines, reduced the lung bacterial burden, and ameliorated the lung injury score. ABL1 inhibited the phosphorylation of IκBα and p38 and regulated the ubiquitination of TRAF6. ABL1 regulates the inflammatory response in pneumonia in part by the regulation of MAPK and NF-κB pathways and TRAF6 ubiquitination.

Cervical sympathetic trunk transection alleviates acute lung injury caused by intestinal obstruction via inhibition of phospholipase A2 in rats

BackgroundIntestinal obstruction can result in inflammatory injury to distant organs, especially the lungs. Stellate ganglion block (SGB) provides sympathetic nervous homeostasis and inhibits the systemic inflammatory response. This study aimed to investigate whether SGB can alleviate acute lung injury by inhibiting phospholipase A2 expression in rats.MethodsThirty healthy male Sprague–Dawley rats were divided into three groups: C group (sham-operated); CLP group (cecal ligation and puncture with intestinal obstruction), and cervical sympathetic trunk transection (CSTT) group (transection of the cervical sympathetic trunk following CLP).Arterial blood samples were obtained to determine the ratio of partial arterial pressure of oxygen (PaO2) to fraction of oxygen in inspired air (FiO2). Venous blood samples were used to evaluate the serum concentrations of chemokines, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 using enzyme-linked immunosorbent assays. Following euthanasia, the lungs were isolated to estimate the wet/dry lung weight (W/D) ratio, evaluate the pathological damage to lung tissues on microscopy, and determine secretory-type phospholipase A2 (sPLA2) expression using western blotting.ResultsRats in the CLP group showed increased fatigue, decreased activity levels, and coarse, gray hair. The levels of chemokines, TNF-α, and IL-6 in the CLP and CSTT groups were higher than those in the C group. However, the levels were lower in the CSTT group than those in the CLP group. IL-10 levels in the CLP group were higher and lower than those in the C and CSTT groups, respectively. W/D ratios and PaO2/FiO2 in the CLP and CSTT groups were higher than those in the C group, whereas these ratios in the CSTT group were lower than those in the CLP group. No lung injury was noted in group C, and the lung injury scores were lower in the CSTT group than those in the CLP group. sPLA2 expression levels in the CLP group were higher than those in the C group, whereas these levels in the CSTT group were lower than those in the CLP group.ConclusionssPLA2 overexpression in the lungs may be a pathogenic factor in acute lung injury. CSTT alleviated acute lung injury by inhibiting sPLA2 expression.

Eupalinolide B attenuates lipopolysaccharide-induced acute lung injury through inhibition of NF-κB and MAPKs signaling by targeting TAK1 protein

Acute lung injury (ALI) is a life-threatening disease characterized by severe inflammatory response, which has no pharmacological therapy in clinic. In this study, we found that eupalinolide B (EB), a sesquiterpene lactone isolated from Eupatorium lindleyanum, significantly ameliorated lipopolysaccharide (LPS)-induced ALI in mice, which manifests as reduction in lung injury score, activity of myeloperoxidase, and release of cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). In RAW264.7 murine macrophages, EB effectively inhibited LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) by down-regulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), respectively. Mechanistically, EB not only blocked LPS-induced phosphorylation of inhibitor of nuclear factor kappa B kinase-α/β (IKKα/β), phosphorylation and degradation of inhibitor of nuclear factor‐kappa B alpha (IκBα), and phosphorylation and nuclear translocation of nuclear factor‐kappa B (NF-κB) P65, but also suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) in vitro or in vivo. Through cellular thermal shift assay and western blotting, EB was demonstrated to target and inactivate transforming growth factor β activated kinase-1 (TAK1), which is an important upstream kinase for the activation of NF-κB and MAPKs pathways. Additionally, EB-mediated actions were markedly abolished by dithiothreitol in LPS-exposed RAW264.7 cells, suggesting a crucial role of the α,γ-unsaturated lactone for the anti-inflammatory activity of EB. In conclusion, our findings showed that EB could effectively alleviate ALI in mice, and attenuate inflammatory response by inhibiting the activation of TAK1, and TAK1-mediated activation of NF-κB and MAPKs cascades.

Antibiotic-induced microbiome depletion improves LPS-induced acute lung injury via gut-lung axis

AimsAcute lung injury (ALI) is an acute inflammatory disorder. However, the precise mechanisms underlying the pathology of ALI remain elusive. An increasing evidence suggests the role of the gut-microbiota axis in the pathology of lung injury. This study aimed to investigate whether antibiotic-induced microbiome depletion could affect ALI in mice after lipopolysaccharide (LPS) administration. Main methodsThe effects of antibiotic cocktail (ABX) on ALI in the mice after intratracheally administration of LPS (5 mg/kg) were examined. Furthermore, 16s rRNA analysis and measurement of short-chain fatty acids in feces samples and metabolomics analysis of blood samples were performed. Key findingsLPS significantly increased the interleukin-6 (IL-6) levels in the bronchoalveolar lavage fluid (BALF) of water-treated mice. Interestingly, an ABX significantly attenuated the LPS-induced increase in IL-6 in BALF and lung injury scores. Furthermore, ABX and/or LPS treatment markedly altered the α- and β-diversity of the gut microbiota. There were significant differences in the α- and β-diversity of the water + LPS group and ABX + LPS group. LEfSe analysis identified Enterococusfaecalis, Clostriumtertium, and Bacteroidescaecimyris as potential microbial markers for ABX + LPS group. Untargeted metabolomics analysis identified several plasma metabolites responsible for discriminating water + LPS group from ABX + LPS group. There were correlations between the relative abundance of the microbiome and plasma metabolites. Integrative network analysis showed correlations between IL-6 levels in BALF and several gut microbes (or plasma metabolites). SignificanceThese data suggest that ABX-induced microbiome depletion could protect against LPS-induced ALI via the gut-microbiota-lung axis.

What are the main factors affecting the outcome of tocilizumab therapy in COVID-19-induced cytokine release syndrome?

Recommendations for the treatment of cytokine release syndrome/macrophage activation syndrome (MAS) associated with coronavirus disease-2019 (COVID-19) are still of poor quality. IL-6 is an important therapeutic target as a main mediator of cytokine storm. The aim of our study was to evaluate the tocilizumab (TCZ) efficacy and factors affecting the therapy outcome. This retrospective study included 27 patients treated with TCZ for COVID-19-MAS. All patients in this study were treated with TCZ (intravenously, at a dose of 8 mg kg1 ) in addition to standard therapy. Clinical improvement (survival and decreased oxygen demand) on the 10-14th days and secondary infection rate were assessed. In our 27 treated patients, 14 (51.8%) received TCZ in the intensive care unit (ICU) and seven (25.9%) were need to invasive mechanical ventilation (IMV). Fifteen (55.6%) of these patients revealed a good clinical response (four patients discharge from the ICU and 11 patients who followed-up in nonICU beds showed a decrease in oxygen demand). TCZ was significantly less effective in patients having high Murray lung injury score, low PO2/FiO2 ratio, IMV, and ICU admission (P < .05). Severity of hypoxemia was found as a single independent risk factor in the multivariable analysis (P < .05). Secondary bacterial infections rate was significantly higher in intubated patients (P < .01) or treated in the ICU (P ¼ .01). TCZ was showed limited efficacy for COVID-19-related MAS. The most important predictive indicator for therapy outcome was found as the severity of hypoxemia. In addition, IMV and/or ICU was associated with the poor outcome and high side effect. So, controlled trials are still needed to confirm the indications and timing of TCZ therapy.

Ulinastatin alleviates pulmonary edema by reducing pulmonary permeability and stimulating alveolar fluid clearance in a rat model of acute lung injury.

Objective(s):Previous studies have shown that ulinastatin (UTI) alleviates pulmonary edema in acute lung injury (ALI) caused by lipopolysaccharide (LPS), although the mechanism behind this action is uncertain. This research aimed to identify the fundamental mechanism by which UTI alleviates pulmonary edema.Materials and Methods:We established a model of acute lung injury (ALI) in rats by using LPS as the inciting agent.The control, LPS, and LPS+UTI groups were each comprised of a specific number of randomly selected Wistar rats. We evaluated lung injury and determined pulmonary edema. The concentrations of TNF-α, IL-1β and IL-6 in BALF and the expression levels of α1Na, k-ATPase, β1Na, K-AtPase, α-ENaC, β-ENaC, γ-ENaC, Zonula occludens (ZO)-1, Occludin, Caludin-5, PI3K, Akt, TLR4, MyD88 and NF-ƘBwere identified in lung tissues.Results:The presence of UTI was associated with a reduction in lung pathological alterations, lung injury scores, the lung W/D ratio, and MPO activity, in addition to the improved gas exchange (P<0.01). Furthermore, UTI alleviated EB leakage and stimulated AFC (P<0.01). Importantly, UTI increased the expression of ZO-1, Occludin, Caludin-5, α1Na, K-ATPase, β1Na, K-AtPase, α-ENaC, β-ENaC, and γ-ENaC (P<0.01). Furthermore, UTI inhibited the inflammatory response, enhanced the expression of PI3K and Akt and hindered TLR4, MyD88, and NF-ƘB expression (P<0.01) in lung tissues.Conclusion: Our results demonstrated that UTI attenuated pulmonary edema by reducing pulmonary permeability and promoting AFC through inhibiting the inflammatory response, and the mechanism is related to promoting PI3K/Akt signaling pathways and suppressing TLR4/MyD88/NF-ƘB signaling pathways.

Andrographolide Derivative AL-1 Ameliorates LPS-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome and Lung Permeability.

Acute lung injury (ALI) is a serious respiratory disease with a high mortality rate, and there is an urgent need for a more effective treatment strategy. Andrographolide derivative AL-1 has been identified to possess anti-inflammatory activity. However, whether it could reduce LPS-induced lung injury in mice through inhibiting NLRP3 inflammasome activation and protecting lung permeability has not yet been elucidated. In the present research, we investigated the protective effect of AL-1 on ALI mice and demonstrated the potential mechanisms. Male Balb/c mice were anesthetized with isoflurane, and ALI mice were induced by intratracheal instillation of LPS. The mice were euthanized after LPS administration for 12 h, then bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The levels of inflammatory factors were measured by ELISA assay, and HE staining and lung injury scoring were used to evaluate the pathological changes in the pulmonary tissues. Immunohistochemistry and immunofluorescence examination were conducted to detect the expression levels of related proteins. Western blot was performed to measure the levels of NLRP3 inflammasome and tight junction proteins. The study indicated that AL-1 effectively alleviated lung injury by reduction of proinflammatory cytokine levels, MPO activity, lung W/D ratio, and total protein levels. Furthermore, AL-1 improved pathological changes in lung tissue and significantly reduced the infiltration of inflammatory cells. Administration with AL-1 markedly inhibited the expression of NLRP3, ASC, Caspase-1, IL-1β, gasdermin D (GSDMD), and VCAM-1 but increased the expression of ZO-1, Occludin, JAM-A, and Claudin-1. Taken together, these results demonstrated that AL-1 ameliorated pulmonary damage by inhibiting the activation of the NLRP3 inflammasome pathway and restoring TJ protein expression.

Salvianolic Acid A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Neutrophil NETosis.

Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.

Clinical efficacy of blood purification using a polymethylmethacrylate hemofilter for the treatment of severe acute pancreatitis.

BackgroundSevere acute pancreatitis (SAP) is a systemic inflammatory disease, and it can often complicate into acute kidney injury (AKI) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS). This study aimed to evaluate the clinical effectiveness of blood purification using a polymethylmethacrylate (PMMA) hemofilter.MethodsWe retrospectively examined 54 patients, who were diagnosed with SAP according to the Japanese criteria from January 2011 to December 2019.ResultsOf a total of 54 SAP patients, 26 patients progressively developed AKI and required continuous hemodialysis with a PMMA membrane hemofilter (PMMA-CHD). Acute Physiology and Chronic Health Evaluation (APACHE) II score and Sequential Organ Failure Assessment (SOFA) score were significantly higher in patients requiring PMMA-CHD than in patients not requiring hemodialysis. The lung injury scores were also significantly higher in patients requiring PMMA-CHD. Of the 26 patients, 16 patients developed ALI/ARDS and required mechanical ventilation. A total of seven patients developed severe ALI/ARDS and received additional intermittent hemodiafiltration using a PMMA hemofilter (PMMA-HDF). Although the length of intensive care unit stay was significantly longer in patients with severe ALI/ARDS, blood purification therapy was discontinued in all the patients. The survival rates at the time of discharge were 92.3% and 92.9% in patients with and without PMMA-CHD, respectively. These real mortality ratios were obviously lower than the estimated mortality ratios predicted by APACHE II scores.ConclusionsThese finding suggest that the blood purification using a PMMA hemofilter would be effective for the treatment of AKI and ALI/ARDS in SAP patients.

The complex lipid, SPPCT-800, reduces lung damage, improves pulmonary function and decreases pro-inflammatory cytokines in the murine LPS-induced acute respiratory distress syndrome (ARDS) model

Context Acute respiratory distress syndrome (ARDS) is a highly fatal, inflammatory condition of lungs with multiple causes. There is no adequate treatment. Objective Using the murine LPS-induced ARDS model, we investigate SPPCT-800 (a complex lipid) as treatment for ARDS. Materials and methods C57B16/N mice received 50 μg of Escherichia coli O111:B4 lipopolysaccharide (LPS). SPPCT-800 was given as either: (1) 20 or 200 mg/kg dose 3 h after LPS; (2) 200 mg/kg (prophylactically) 30 min before LPS; or (3) eight 200 mg/kg treatments over 72 h. Controls received saline installations. Results At 48 and 72 h, SpO2 was 94% and 90% in controls compared to 97% and 94% in treated animals. Expiration times, at 24 and 48 h, were 160 and 137 msec for controls, but 139 and 107 msec with SPPCT-800. In BALF (24 h), cell counts were 4.7 × 106 (controls) and 2.9 × 106 (treated); protein levels were 1.5 mg (controls) and 0.4 mg (treated); and IL-6 was 942 ± 194 pg/mL (controls) versus 850 ± 212 pg/mL (treated) [at 72 h, 4664 ± 2591 pg/mL (controls) versus 276 ± 151 pg/mL (treated)]. Weight losses, at 48 and 72 h, were 20% and 18% (controls), but 14% and 8% (treated). Lung injury scores, at 24 and 72 h, were 1.4 and 3.0 (controls) and 0.3 and 2.2 (treated). Discussion and conclusions SPPCT-800 was effective in reducing manifestations of ARDS. SPPCT-800 should be further investigated as therapy for ARDS, especially in longer duration or higher cumulative dose studies.

Outcome of post-traumatic acute respiratory distress syndrome in young patients requiring extracorporeal membrane oxygenation (ECMO)

We aimed to evaluate the outcomes of post-traumatic acute respiratory distress syndrome (ARDS) in young patients with and without Extracorporeal membrane oxygenation (ECMO) support. A retrospective analysis was conducted for trauma patients who developed ARDS at a level I trauma facility between 2014 and 2020. Data were analyzed and compared between ECMO and non-ECMO group. We identified 85 patients with ARDS (22 patients had ECMO support and 63 matched patients managed by the conventional mechanical ventilation; 1:3 matching ratio). The two groups were comparable for age, sex, injury severity score, abbreviated injury score, shock index, SOFA score, and head injury. Kaplan Meier survival analysis showed that the survival in the ECMO group was initially close to that of the non-ECMO, however, during follow-up, the survival rate was better in the ECMO group, but did not reach statistical significance (Log-rank, p = 0.43 and Tarone-Ware, p = 0.37). Multivariable logistic regression analysis showed that acute kidney injury (AKI) (Odds ratio 13.03; 95% CI 3.17–53.54) and brain edema (Odds ratio 4.80; 95% CI 1.10–21.03) were independent predictors of mortality. Sub-analysis showed that in patients with severe Murray Lung Injury (MLI) scores, non-ECMO group had higher mortality than the ECMO group (100% vs 36.8%, p = 0.004). Although ARDS is uncommon in young trauma patients, it has a high mortality. ECMO therapy was used in a quarter of ARDS cases. AKI and brain edema were the predictors of mortality among ARDS patients. ECMO use did not worsen the outcome in trauma patients; however, the survival was better in those who had severe MLI and ECMO support. Further prospective study is needed to define the appropriate selection criteria for the use of ECMO to optimize the outcomes in trauma patients.

Ginkgolide C Alleviates Acute Lung Injury Caused by Paraquat Poisoning via Regulating the Nrf2 and NF-κB Signaling Pathways.

Paraquat (PQ), a highly toxic herbicide and primary attack for lung, results in severe acute lung injury (ALI) appeared as evident oxidative stress, inflammation, and apoptosis. Increasing evidence elucidates that nuclear factor erythroid-2-related factor 2 (Nrf2) and its associated nuclear factor-κB (NF-κB) exhibit many merits for protection of ALI by coordinating a fine-turned response to oxidative stress, inflammation, and apoptosis. Ginkgolide C (GC) has been reported to be a safe and potent therapeutic agent against ALI. However, whether GC could protect ALI induced by PQ poisoning and the possible underlining mechanisms have remained not to be fully elucidated. A rat model of ALI and a model of acute type II alveolar epithelial cell (RLE-6TN) injury constructed by exposure to PQ were applied to discuss the protective effect of GC. Furthermore, Nrf2 gene silencing RLE-6TN cells were used to discuss the exact mechanism. We confirmed that GC significantly ameliorated the histopathological damages, ultrastructural changes, lung injury score, W/D ratio, and Hyp activity of lung tissue and inhibited polymorphonuclear neutrophil (PMN) infiltration after PQ poisoning. Further results revealed that GC remarkably activated Nrf2-based cytoprotective system and inhibited NF-κB-induced inflammatory injury as well as apoptosis. Taken together, we concluded that GC preserved protection of PQ-induced ALI via the Nrf2-NF-κB dependent signal pathway, which may provide us novel insights into the treatment strategies for PQ poisoning.

Exaggerated Ventilator-Induced Lung Injury in an Animal Model of Type 2 Diabetes Mellitus: A Randomized Experimental Study.

Although ventilator-induced lung injury (VILI) often develops after prolonged mechanical ventilation in normal lungs, pulmonary disorders may aggravate the development of adverse symptoms. VILI exaggeration can be anticipated in type 2 diabetes mellitus (T2DM) due to its adverse pulmonary consequences. Therefore, we determined whether T2DM modulates VILI and evaluated how T2DM therapy affects adverse pulmonary changes. Rats were randomly assigned into the untreated T2DM group receiving low-dose streptozotocin with high-fat diet (T2DM, n = 8), T2DM group supplemented with metformin therapy (MET, n = 8), and control group (CTRL, n = 8). In each animal, VILI was induced by mechanical ventilation for 4 h with high tidal volume (23 ml/kg) and low positive end-expiratory pressure (0 cmH2O). Arterial and venous blood samples were analyzed to measure the arterial partial pressure of oxygen (PaO2), oxygen saturation (SaO2), and the intrapulmonary shunt fraction (Qs/Qt). Airway and respiratory tissue mechanics were evaluated by forced oscillations. Lung histology samples were analyzed to determine injury level. Significant worsening of VILI, in terms of PaO2, SaO2, and Qs/Qt, was observed in the T2DM group, without differences in the respiratory mechanics. These functional changes were also reflected in lung injury score. The MET group showed no difference compared with the CTRL group. Gas exchange impairment without significant mechanical changes suggests that untreated diabetes exaggerates VILI by augmenting the damage of the alveolar–capillary barrier. Controlled hyperglycemia with metformin may reduce the manifestations of respiratory defects during prolonged mechanical ventilation.

Role and mechanism of signal transducer and activator of transcription protein STAT1/3/5 in hyperoxia-induced acute lung injury

To investigate whether signal transducer and activator of transcription (STAT1/3/5) have a protective effect on hyperoxia-induced acute lung injury (HALI) and its mechanism. Seventy C57BL/6J mice were randomly divided into five groups: normoxia control group, HALI group, and STAT1/3/5 inhibitor groups, with 14 mice in each group. The HALI model was established by exposure to more than 90% hyperoxia for 48 hours; three STAT inhibitor groups were pretreated by intraperitoneal injection of STAT1 inhibitor 40 mg/kg and STAT3 inhibitor 5 mg/kg, and STAT5 inhibitor 10 mg/kg for 1 week. Six blood samples were randomly collected from each group, and microRNA-21 (miR-21) expression was measured by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). Lung tissue of the sacrificed mice was obtained, and enzyme linked immunosorbent assay (ELISA) was used to detect the contents of tumor necrosis factor-α (TNF-α), interleukins (IL-6, IL-1β), superoxide dismutase (SOD), malonic dialdehyde (MDA), and matrix metalloproteinase 9 (MMP9). The water content of lung tissue was calculated. The pathological changes in lung tissue were observed under the light microscope, and the pathological score of lung injury was performed. Western blotting was used to detect the expression of phosphorylated STAT (p-STAT1, p-STAT3, p-STAT5) in lung tissue. The 7-day cumulative survival rates of the remaining 8 mice in each group were analyzed using Kaplan-Meier survival curves. Under the light microscope, the alveolar structures in the HALI group and the STAT1 inhibitor group were destroyed, a large number of neutrophils (NEU) infiltrated in the alveoli and lung interstitium, which were thickened. The pathological score of lung injury and the water content of the lung tissue was significantly increased. In STAT3 inhibitor and STAT5 inhibitor groups, the alveolar cavity was clear, the degree of NEU infiltration and the thickness of lung interstitium were lower than those in HALI group, the pathological score of lung injury and the water content of lung tissue were significantly decreased, especially in STAT3 inhibitor group. Compared with the normoxia control group, the contents of TNF-α, IL-6, IL-1β, MDA, and MMP9, and the expression levels of p-STAT3 and p-STAT5 in the HALI group were significantly increased. In contrast, the content of SOD and the expression of miR-21 were significantly decreased. Compared with the HALI group, the contents of TNF-α, IL-6, IL-1β, MDA, and MMP9 in the STAT3 inhibitor group and STAT5 inhibitor group were significantly decreased. At the same time, the content of SOD and the expression of miR-21 were significantly increased, especially in STAT3 inhibitor group [TNF-α (μg/L): 42.53±3.25 vs. 86.36±5.48, IL-6 (ng/L): 68.46±4.28 vs. 145.00±6.89, IL-1β (μg/L): 28.74±3.53 vs. 68.00±5.64, MDA (μmol/g): 20.33±2.74 vs. 42.58±3.45, and MMP9 (ng/L): 128.55±6.35 vs. 325.13±6.65, SOD (kU/g): 50.53±4.19 vs. 22.53±3.27, miR-21 (2-ΔΔCt): 0.550±0.018 vs. 0.316±0.037, all P < 0.05]. Kaplan-Meier survival curve analysis showed that the 7-day cumulative survival rates of the STAT3 inhibitor group and STAT5 inhibitor group were significantly higher than those of the HALI group [62.5% (5/8), 37.5% (3/8) vs. 12.5% (1/8), both P < 0.05]. Inhibition of STAT3 hyperactivation may suppress the inflammatory response, regulate oxidative stress, improve lung permeability through regulating the expression of miR-21, which exert lung protection in HALI.

Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling

BackgroundAcute lung injury (ALI) caused by intestinal ischemia–reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor that participates in the initiation of the inflammatory response. This study aims to establish whether C-176 (STING inhibitor) improves ALI under intestinal ischemia–reperfusion conditions.MethodsTo induce ALI, 72 male C57BL/6 mice were subjected to intestinal ischemia for 60 min and reperfusion for 3 h. Through intraperitoneal injection, C-176, a selective STING inhibitor, was injected 30 min before surgical treatment; meanwhile, compound C, an antagonist of adenosine monophosphate-activated protein kinase (AMPK), was administered 30 min after surgery. Based on immunofluorescence and Western blot assays, post-ALI assessments included lung water content (TLW), bronchoalveolar lavage fluid (BALF) protein, H&E staining, Masson staining, pulmonary pyroptosis [Gasdermin-D (GSDMD), cleaved caspase-1], and apoptosis (TUNEL, cleaved caspase-3).ResultsC-176 administration significantly attenuated intestinal ischemia–reperfusion-mediated ALI; this effect was reflected by exacerbated TLW and BALF protein, aggravated lung injury score, elevated degree of pulmonary fibrosis, increased TUNEL- and GSDMD-positive cells, and upregulated phospho-AMPK, cleaved caspase-1, cleaved caspase-3 and IFNβ mRNA expression. Moreover, C-176 increased phospho-AMPK under ALI conditions. Nonetheless, compound C partially reversed these beneficial effects.ConclusionC-176, a selective STING inhibitor, improves intestinal ischemia–reperfusion-mediated ALI, and its underlying mechanism may be associated with AMPK signal activation.