Variable positive end-expiratory pressure in an experimental model of acute respiratory distress syndrome: an advanced ventilation modality.

Background: Introducing variability in tidal volume, ventilatory frequency, or both is beneficial during mechanical ventilation in acute respiratory distress syndrome (ARDS). We investigated whether applying cycle-by-cycle variability in the positive end-expiratory pressure (PEEP) exerts beneficial effect on lung function in a model of ARDS. Methods: Rabbits with lung injury were randomly allocated to receive mechanical ventilation for 6 h by applying a pressure-controlled mode with constant PEEP of 7 cm H2O (PC group: n=6) or variable PEEP (VEEP) with a coefficient of variation of 21.4%, range 4-10 cm H2O (PC-VEEP group; n=6). Lung oxygenation index (Pao2/FiO2) after 6 h of ventilation (H6) was the primary outcome and respiratory mechanics, lung volume, intrapulmonary shunt, and lung inflammatory markers were secondary outcomes. Results: After lung injury, both groups presented moderate-to-severe ARDS (Pao2/FiO2 <27 kPa). The Pao2/FiO2 was significantly higher in the PC-VEEP group than in the PC group at H6 (12.3 [sd 3.5] vs 19.2 [7.2] kPa, P=0.013) and a lower arterial partial pressure of CO2 at 1-3 h (P<0.02). The ventilation-induced increases in airway resistance and tissue elastance were prevented by PC-VEEP. There was no evidence for a difference in minute volume, driving pressure, end-tidal CO2, lung volumes, intrapulmonary shunt fraction, and cytokines between the ventilation modes. Conclusions: Prolonged mechanical ventilation with cycle-by-cycle VEEP prevents deterioration in gas exchange and respiratory mechanics in a model of ARDS, suggesting the benefit of this novel ventilation strategy to optimise gas exchange without increasing driving pressure and lung overdistension.

BRD3308 suppresses macrophage oxidative stress and pyroptosis via upregulating acetylation of H3K27 in sepsis-induced acute lung injury.

Background: Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival. Methods: In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes. Results: BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy. Conclusions: BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI.

Resolvin E1 and Inhibition of BLT2 Signaling Attenuate the Inflammatory Response and Improve One-Lung Ventilation-Induced Lung Injury.

INTRODUCTION: One-lung ventilation (OLV) is a prevalently used technique to sustain intraoperative pulmonary function. Resolvin E1 (RvE1), a specialized pro-resolving lipid mediator, accelerates the resolution of inflammation in the lungs. However, its therapeutic effects on OLV-induced lung injury remain unclear. METHODS: We initially developed an OLV rat model and treated it with RvE1. Subsequently, we assessed the wet/dry ratio of the lung tissue, performed hematoxylin and eosin staining, and calculated the ratio of polymorphonuclear cells to white blood cells in the bronchoalveolar lavage fluid. Additionally, we assessed apoptosis, inflammatory factor levels, and lung permeability in the rat lung tissues in the RvE1 treated and untreated groups and explored the molecular mechanisms mediated by RvE1. RESULTS: Our results indicated that RvE1 alleviated lung injury and inflammation and improved lung tissue apoptosis and permeability in OLV rats. Moreover, RvE1 suppressed the expression of the BLT1/2 signaling pathway and its ligands. The use of BLT2 and BLT1 inhibitors (LY255283 and U-75302, respectively) enhanced RvE1's anti-inflammatory effects and reduced lung injury. Furthermore, synergistic treatment with the BLT2 inhibitor and RvE1 provided grater benefits by more effectively inhibiting the NF-kB, p38 MAPK, and ERK pathways. DISCUSSION: RvE1 and the inhibition of BLT2 signalling reduce the inflammatory response and mitigate OLV-induced lung injury. These findings suggest a novel therapeutic pathway for managing OLV-related complications.

Sodium Houttuyniae attenuates ferroptosis by regulating TRAF6-c-Myc signaling pathways in lipopolysaccharide-induced acute lung injury (ALI).

The impact of Sodium Houttuyniae (SH) on lipopolysaccharide (LPS)-induced ALI has been investigated extensively. However, it remains ambiguous whether ferroptosis participates in this process. This study aimed to find out the impacts and probable mechanisms of SH on LPS-induced ferroptosis. A rat ALI model and type II alveolar epithelial (ATII) cell injury model were treated with LPS. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, and Giemsa staining were executed to ascertain the effects of SH on LPS-induced ALI. Moreover, Transmission electron microscopy, Cell Counting Kit-8 (CCK8), ferrous iron colorimetric assay kit, Immunohistochemistry, Immunofluorescence, Reactive oxygen species assay kit, western blotting (Wb), and qRT-PCR examined the impacts of SH on LPS-induced ferroptosis and ferroptosis-related pathways. Theresults found that by using SH treatment, there was a remarkable attenuation of ALI by suppressing LPS-induced ferroptosis. Ferroptosis was demonstrated by a decline in the levels of glutathione peroxidase 4 (GPX4), FTH1, and glutathione (GSH) and a surge in the accumulation of malondialdehyde (MDA), reactive oxygen species (ROS), NOX1, NCOA4, and Fe2+, and disruption of mitochondrial structure, which were reversed by SH treatment. SH suppressed ferroptosis by regulating TRAF6-c-Myc in ALI rats and rat ATII cells. The results suggested that SH treatment attenuated LPS-induced ALI by repressing ferroptosis, and the mode of action can be linked to regulating the TRAF6-c-Myc signaling pathway in vivo and in vitro.

Sulfotransferase homolog 2 receptors blockade on monocyte subsets along with their inflammatory cytokines for septic lung injury.

PURPOSE OF THE STUDY: To observe the dynamic changes in monocyte subsets during septic lung injury and to assess the anti-inflammatory role of the sulfotransferase homolog 2 (ST2) receptor. MATERIALS AND METHODS: Dynamic changes of monocyte subsets from patients with septic lung injury and mice post-cecal ligation and puncture (CLP) were monitored. ST2 receptors on mice monocytes and concentrations of IL-33, IL-1ß, IL-12, and IL-27 from peripheral blood or culture supernatant were detected. RESULTS: CD14lowCD16- (Mo0) and CD14++CD16+ (Mo2) monocyte subsets were significantly expanded in patients with sepsis-related acute respiratory distress syndrome. In sepsis model mice, monocyte counts, particularly of Ly6Cint and CDLy6Cint+hi monocytes, were significantly increased. The mean optical density value of TNF-α after CLP mainly increased after 24 h, whereas that of IL-6 was significantly increased at all time points assessed after CLP. The levels of IL-1ß, IL-12, IL-27, and IL-33 increased to variable degrees at 6, 12, 24, and 48h after CLP, and ST2+ monocytes were significantly expanded in sepsis model mice compared to sham-operated mice. ST2 receptor blockade suppressed IL-1ß and IL-12 production in cell culture. CONCLUSIONS: Changes in monocyte subsets expressing the ST2 receptor play an important role in septic lung injury by modulating inflammatory cytokine secretion.

Electronic cigarettes: "wolves in sheep's clothing".

OBJECTIVE: To provide cutting-edge information on the impact and risks of using Electronic Nicotine Delivery Systems (ENDS) by children and adolescents, based on the latest evidence published in the literature. DATA SOURCE: A comprehensive search was carried out on PubMed, using the expressions ''electronic cigarettes'' OR ''electronic nicotine delivery systems" OR "vaping" AND ''adolescent'' AND "risks" AND ''acute lung injury'. All retrieved articles had their titles and abstracts read to identify and fully read the papers reporting the most recent evidence on each subject. SUMMARY OF FINDINGS: The use of ENDS has alarmingly increased in Brazil and around the world. The possibility of customizing use, the choice of flavors and nicotine content, and the general notion that these devices are harmless when compared to conventional cigarettes are some of the factors responsible for this increase. Numerous scientific studies have proven that electronic cigarettes have serious consequences for the respiratory system, such as EVALI (E-cigarette or Vaping-Associated Lung Injury) and difficult-to-control asthma, as well as harmful effects on the neurological, cardiovascular, gastrointestinal, and immunological systems. High concentrations of nicotine make many young people addicted to this substance. In Brazil, commercialization, import, and advertising are prohibited. The viable interventions to address the use of these devices in children and adolescents are prevention and behavioral counseling. CONCLUSION: There is clear scientific evidence that these devices pose a risk to the physical and mental health of children and adolescents.

The preventive effectiveness of Crocus sativus extract in treating lung injuries caused by inhaled paraquat in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The herbicide paraquat (PQ) is highly toxic, capable of inducing severe lung inflammation and oxidative stress, resulting in lung fibrosis and respiratory failure. Previous research has demonstrated a range of pharmacological effects associated with Crocus sativus. L (Cs) through its anti-inflammatory, antioxidant and immunomodulatory properties. Pharmacological studies support the widespread use of Cs in traditional medicine to treat respiratory disorders such as coughs and asthma. AIM OF STUDY: This study aimed to investigate the preventive impact of Cs extract and pioglitazone (Pio) on lung inflammation, oxidative stress, pathological alterations, and tracheal reactivity induced by inhaled PQ in rats as compared to dexamethasone (Dexa). METHODS: The control (Ctrl) group of rats was administered with saline aerosol, while the remaining six groups received PQ aerosol eight times every other day. The six PQ exposure groups were treated daily during the exposure period to PQ with either; saline alone, low dose Cs, High dose Cs, Pio alone, Pio combined with low dose Cs, or Dexa of 16 days. RESULTS: In the PQ group, the levels of superoxide dismutase (SOD), catalase (CAT), and thiol in the bronchoalveolar lavage fluid (BALF) were declined whereas, the levels of MDA, total and differential WBC, and lung tissue levels of tumor necrosis factor (TNF-α) and Interleukin 10 (IL-10), tracheal responsiveness (TR) to methacholine and lung pathological changes were enhanced. The measured variables showed significant improvement in all treated groups, except for a few variables in Cs (L). The combined Cs (L) + Pio showed higher effects than Cs (L) and Pio alone. For all comparisons, p values were <0.05 to <0.001. CONCLUSIONS: The results showed preventive effect of Cs comparable to that of Dexa and the potential additive preventive capabilities of the Cs and Pio indicate that the involvement of the PPARγ receptor is implicated in the effects induced by Cs.

Effectiveness of remote ischaemic conditioning is not affected by hyper-inflammation in a rat model of stroke.

The inflammation and coagulopathy during coronavirus disease (COVID-19) impairs the efficiency of the current stroke treatments. Remote ischaemic conditioning (RIC) has shown potential in recent years to protect the brain and other organs against pathological conditions. This study aimed to evaluate the efficiency of RIC in brain infarct size using TTC staining and lung injury reduction by H&E staining during the hyper-inflammatory response in rats. The inflammation and coagulopathy were assessed by sedimentation rate, haematocrit, systemic oxidative stress and clotting time. Moreover, we observed changes in the cytokine profile. The results of the first part of the experiment showed that the inflammation and lung injury are fully developed after 24 h of intratracheal LPS administration. At this time, we induced focal brain ischaemia and examined the effect of RIC pre- and post-treatment. Our results showed that RIPre-C reduced the infarct size by about 23%, while RIPost-C by about 30%. The lung injury was also reduced following both treatments. Moreover, RIC modulated systemic inflammation. The level of chemokines CINC-1, LIX and RANTES decreased after 24 h of post-ischaemic reperfusion in treated animals compared to non-treated. The RIC-mediated decrease of inflammation was reflected in improved sedimentation rate and hematocrit, as well as reduced systemic oxidative stress. The results of this work showed neuroprotective and lung protective effects of RIC with a decrease in inflammation response. On the basis of our results, we assume that immunomodulation through the chemokines CINC-1, LIX, and RANTES play a role in RIC-mediated protection.

Impact of time intervals on drug efficacy and phenotypic outcomes in acute respiratory distress syndrome in mice.

Acute respiratory distress syndrome is a severe lung condition resulting from various causes, with life-threatening consequences that necessitate intensive care. The phenomenon can be modeled in preclinical models, notably through the use of lipopolysaccharide (LPS) instillation in mice. The phenotype induced closely recapitulates the human syndrome, including pulmonary edema, leukocyte infiltration, acute inflammation, impaired pulmonary function, and histological damage. However, the experimental designs using LPS instillations are extremely diverse in the literature. This highly complicates the interpretation of the induced phenotype chronology for future study design and hinders the proper identification of the optimal time frame to assess different readouts. Therefore, the definition of the treatment window in relation to the beginning of the disease onset also presents a significant challenge to address questions or test compound efficacy. In this context, the temporality of the different readouts usually measured in the model was evaluated in both normal and neutrophil-depleted male C57bl/6 mice using LPS-induction to assess the best window for proper readout evaluation with an optimal dynamic response range. Ventilation parameters were evaluated by whole-body plethysmography and neutrophil recruitment were evaluated in bronchoalveolar lavage fluids and in lung tissues directly. Imaging evaluation of myeloperoxidase along with activity in lung lysates and fluids were compared, along with inflammatory cytokines and lung extravasation by enzyme-linked immunoassays. Moreover, dexamethasone, the gold standard positive control in this model, was also administered at different times before and after phenotype induction to assess how kinetics affected each parameter. Overall, our data demonstrate that each readout evaluated in this study has a singular kinetic and highlights the key importance of the timing between ARDS phenotype and treatment administration and/or analysis. These findings also strongly suggest that analyzes, both in-life and post-mortem should be conducted at multiple time points to properly capture the dynamic phenotype of the LPS-ARDS model and response to treatment.

Transforming growth factor-ß1 is associated with inflammatory resolution via regulating macrophage polarization in lung injury model mice.

OBJECTIVE: Ventilation is the main respiratory support therapy for acute respiratory distress syndrome, which triggers acute lung injury (ALI). Macrophage polarization is vital for the resolution of inflammation and tissue injury. We hypothesized that transforming growth factor (TGF)-ß1 may attenuate inflammation and ventilator-induced ALI by promoting M2 macrophage polarization. METHODS: C57BL/6 mice received 4-hour ventilation and extubation to observe the resolution of lung injury and inflammation. Lung vascular permeability, inflammation, and histological changes in the lungs were evaluated by bronchoalveolar lavage analysis, enzyme linked immunosorbent assay, hematoxylin and eosin staining, as well as transmission electron microscope. TGF-ß1 cellular production and macrophage subsets were analyzed by flow cytometry. The relative expressions of targeted proteins and genes were measured by immunofuorescence staining, Western blot, and quantitative polymerase chain reaction. RESULTS: High tidal volume-induced injury and inflammation were resolved at 3 days of post-ventilation (PV3d) to PV10d, with increased elastic fibers, proteoglycans, and collagen content, as well as higher TGF-ß1 levels. M1 macrophages were increased in the acute phase, whereas M2a macrophages began to increase from PV1d to PV3d, as well as increased M2c macrophages from PV3d to PV7d. A single dose of rTGF-ß1 attenuated lung injury and inflammation at end of ventilation with polymorphonuclear leukocyte apoptosis, while nTAb pretreatment induced the abnormal elevation of TGF-ß1 that aggravated lung injury and inflammation due to the significant inhibition of M1 macrophages polarized to M2a, M2b, and M2c macrophages. CONCLUSIONS: Precise secretion of TGF-ß1-mediated macrophage polarization plays a crucial role in the resolution of ventilator-induced inflammatory lung injury.

Atomic Artificial Enzyme for Acute and Chronic Pneumonia.

Pneumonia involves complex immunological and pathological processes leading to pulmonary dysfunction, which can be life-threatening yet lacks effective specialized medications. Natural enzymes can be used as biological agents for the treatment of oxidative stress-related diseases, but limiting to catalytic and environmental stability as well as high cost. Herein, an artificial enzyme, gold nanoclusters (Au NCs) with excellent stability, bioactivity, and renal clearance can be used as the next-generation biological agents for acute lung injury (ALI) and allergic lung disease (ALD). The Au25 clusters can mimic catalase (CAT) and glutathione peroxidase (GPx), and the Km of Au24Er1 with H2O2 reaches 1.28 mM, about 22 times higher than natural CAT (≈28.8 mM). The clusters inhibit the oxidative stress in the mitochondria and promote the synthesis of adenosine triphosphate (ATP). The molecular mechanism shows that the TLR4/MyD88/NF-κB pathway and M1 macrophage-mediated inflammatory response are suppressed in ALI and the Th1/Th2 imbalance in ovalbumin (OVA)-induced ALD is rescued. Further, the clusters can notably improve lung function in both ALI and ALD models which paves the way for immunomodulation and intervention for lung injury and can be used as a substitute for natural enzymes and potential biopharmaceuticals in the treatment of various types of pneumonia.

Systemic and Lung Inflammation and Oxidative Stress Associated With Behavioral Changes Induced by Inhaled Paraquat Are Ameliorated by Carvacrol.

Paraquat (PQ) is an herbicide toxin that induces injury in different organs. The anti-inflammatory and antioxidant effects of carvacrol were reported previously. The effects of carvacrol and pioglitazone (Pio) alone and their combination on inhaled PQ-induced systemic and lung oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (control [Ctrl]) or PQ (PQ groups) aerosols. PQ-exposed animals were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day carvacrol (C-L and C-H), 5 mg/kg/day Pio, and Pio+C-L for 16 days. Inhaled PQ markedly enhanced total and differential white blood cell (WBC) counts, nitric oxide (NO), and malondialdehyde (MDA) levels but decreased catalase (CAT) and superoxide dismutase (SOD) activities and thiol levels both in the bronchoalveolar lavage fluid (BALF) and blood and increased interferon-gamma (INF-γ) and interleukin-10 (IL-10) levels in the BALF (p < 0.001 for all cases) except lymphocyte count in blood which was not significantly changed. The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the Morris water maze (MWM) test and the duration of time latency in the dark room in the shuttle box test were reduced after receiving an electrical shock (p < 0.05-p < 0.001). Inhaled PQ-induced changes were significantly improved in carvacrol, Pio, Dexa, and especially in the combination of the Pio+C-L treated groups (p < 0.05-p < 0.001). Carvacrol and Pio improved PQ-induced changes similar to Dexa, but ameliorative effects produced by combination treatments of Pio+C-L were more prominent than Pio and C-L alone, suggesting a potentiating effect for the combination of the two agents.

Acute Lung Injury Caused by Mugwort Steaming.

Mugwort steaming is a traditional health practice with reported biological benefits, but its potential adverse effects on lung health remain unexplored. We report a case of a 48-year-old Japanese female who developed recurrent respiratory symptoms and abnormal lung shadows following occupational exposure to mugwort steaming. Initial diagnosis suggested nonfibrotic hypersensitivity pneumonitis. However, transbronchial lung cryobiopsy revealed findings consistent with acute lung injury (ALI). Multi-disciplinary discussion led to a final diagnosis of ALI caused by mugwort steaming. The patient's condition improved when mugwort steaming was discontinued. This case represents the first reported instance of ALI associated with mugwort steaming. It highlights the need for caution in traditional practices and emphasizes the importance of considering unconventional exposures in unexplained lung pathologies. Further research is warranted to establish the safety profile and potential risks of mugwort steaming.

Inflammatory signature-based theranostics for acute lung injury in acute type A aortic dissection.

Acute lung injury (ALI) is a serious adverse event in the management of acute type A aortic dissection (ATAAD). Using a large-scale cohort, we applied artificial intelligence-driven approach to stratify patients with different outcomes and treatment responses. A total of 2,499 patients from China 5A study database (2016-2022) from 10 cardiovascular centers were divided into 70% for derivation cohort and 30% for validation cohort, in which extreme gradient boosting algorithm was used to develop ALI risk model. Logistic regression was used to assess the risk under anti-inflammatory strategies in different risk probability. Eight top features of importance (leukocyte, platelet, hemoglobin, base excess, age, creatinine, glucose, and left ventricular end-diastolic dimension) were used to develop and validate an ALI risk model, with adequate discrimination ability regarding area under the receiver operating characteristic curve of 0.844 and 0.799 in the derivation and validation cohort, respectively. By the individualized treatment effect prediction, ulinastatin use was significantly associated with significantly lower risk of developing ALI (odds ratio [OR] 0.623 [95% CI 0.456, 0.851]; P = 0.003) in patients with a predicted ALI risk of 32.5-73.0%, rather than in pooled patients with a risk of <32.5 and >73.0% (OR 0.929 [0.682, 1.267], P = 0.642) (Pinteraction = 0.075). An artificial intelligence-driven risk stratification of ALI following ATAAD surgery were developed and validated, and subgroup analysis showed the heterogeneity of anti-inflammatory pharmacotherapy, which suggested individualized anti-inflammatory strategies in different risk probability of ALI.

Transfusion-related acute lung injury (TRALI) following intravenous immunoglobulin infusion in a rituximab immunosuppressed patient with long-shedding SARS-CoV-2.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported. CASE PRESENTATION: A 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI. CONCLUSION: IVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected.

Vaping-associated illness: a reassessment.

BACKGROUND: In 2019, there was widespread presentation of respiratory distress as well as other organ system involvement in patients with a history of vaping. There continue to be reports of vaping-associated illness (VAI). This has come to be known as e-cigarette and vaping product associated lung injury (EVALI). The mechanism of injury remains unclear. OBJECTIVES: This study reexamines the clinical characteristics of patients affected by vaping and suggests that lung injury may not be the primary organ dysfunction but be part of a larger systemic illness. METHODS: This is a retrospective chart review of all patients presenting to one hospital identified as having vaping-associated illness RESULTS: Fourteen patients were identified ranging in age from 15 to 33 years. Patients had a broad range of clinical severity. Respiratory symptoms occurred in 64%, gastrointestinal symptoms in 57%, fever in 78%, neurological symptoms in 15% and other constitutional symptoms in 50%. 35% presented with no respiratory symptoms. CONCLUSION: While the lungs are certainly involved in vaping-associated illness, recognizing the extent of involvement of other organ systems may provide insight into the pathophysiology of the disease. Providers should be aware that vaping-associated illness presents with a multitude of symptoms outside of lung injury, such as abdominal pain, headache or even fever.

Mechanism of KLF2 in young mice with pneumonia induced by Streptococcus pneumoniae.

BACKGROUND: Streptococcus pneumoniae (Spn) is a major causative agent of pneumonia, which can disseminate to the bloodstream and brain. Pneumonia remains a leading cause of death among children aged 1-59 months worldwide. This study aims to investigate the role of Kruppel-like factor 2 (KLF2) in lung injury caused by Spn in young mice. METHODS: Young mice were infected with Spn to induce pneumonia, and the bacterial load in the bronchoalveolar lavage fluid was quantified. KLF2 expression in lung tissues was analyzed using real-time quantitative polymerase chain reaction and Western blotting assays. Following KLF2 overexpression, lung tissues were assessed for lung wet-to-dry weight ratio and Myeloperoxidase activity. The effects of KLF2 on lung injury and inflammation were evaluated through hematoxylin and eosin staining and enzyme-linked immunosorbent assay. Chromatin immunoprecipitation and dual-luciferase assay were conducted to examine the binding of KLF2 to the promoter of microRNA (miR)-222-3p and cyclin-dependent kinase inhibitor 1B (CDKN1B), as well as the binding of miR-222-3p to CDKN1B. Levels of miR-222-3p and CDKN1B in lung tissues were also determined. RESULTS: In young mice with pneumonia, KLF2 and CDKN1B were downregulated, while miR-222-3p was upregulated in lung tissues. Overexpression of KLF2 reduced lung injury and inflammation, evidenced by decreased bacterial load, reduced lung injury, and lower levels of proinflammatory factors. Co-transfection of miR-222-3p-WT and oe-KLF2 significantly reduced luciferase activity, suggesting that KLF2 binds to the promoter of miR-222-3p and suppresses its expression. Transfection of CDKN1B-WT with miR-222-3p mimics significantly reduced luciferase activity, indicating that miR-222-3p binds to CDKN1B and downregulates its expression. Overexpression of miR-222-3p or downregulation of CDKN1B increased bacterial load in BALF, lung wet/dry weight ratio, MPO activity, and inflammation, thereby reversing the protective effect of KLF2 overexpression on lung injury in young mice with pneumonia. CONCLUSIONS: KLF2 alleviates lung injury in young mice with Spn-induced pneumonia by transcriptional regulation of the miR-222-3p/CDKN1B axis.

VEGFR1 TK signaling protects the lungs against LPS-induced injury by suppressing the activity of alveolar macrophages and enhancing the anti-inflammatory function of monocyte-derived macrophages.

Acute lung injury (ALI) is characterized by hyperinflammation followed by vascular leakage and respiratory failure. Vascular endothelial growth factor (VEGF)-A is critical for capillary permeability; however, the role of VEGF receptor 1 (VEGFR1) signaling in ALI progression remains unclear. Here, we show that deletion of VEGFR1 tyrosine kinase (TK) signaling in mice exacerbates lipopolysaccharide (LPS)-induced ALI as evidenced by excessive pro-inflammatory cytokine production and interleukin(IL)-1ß-producing neutrophil recruitment to inflamed lung tissues. ALI development involves reduced alveolar macrophage (AM) levels and recruitment of monocyte-derived macrophages (MDMs) in a VEGFR1 TK-dependent manner. VEGFR1 TK signaling reduced pro-inflammatory cytokine levels in cultured AMs. VEGFR1 TK-expressing MDMs displayed an anti-inflammatory macrophage phenotype. Additionally, the transplantation of VEGFR1 TK-expressing bone marrow (BM)-derived macrophages into VEGFR1 TK-deficient mice reduced lung inflammation. Treatment with placental growth factor (PlGF), an agonist for VEGFR1, protected the lung against LPS-induced ALI associated with increased MDMs. These results suggest that VEGFR1 TK signaling prevents LPS-induced ALI by suppressing the pro-inflammatory activity of AMs and enhancing the anti-inflammatory function of MDMs.

Exosomal Drug Delivery Systems: A Novel Therapy Targeting PD-1 in Septic-ALI.

BACKGROUND: The cytokine storm triggered by sepsis can lead to the development of acute lung injury (ALI). Human umbilical cord Mesenchymal stem cells derived exosomes (HucMSCs-EXOs) have been demonstrated to possess immunosuppressive and anti-inflammatory properties. Programmed cell death receptor 1 (PD-1) plays a crucial role in maintaining the inflammatory immune homeostasis. The aim of this study is to investigate the synergistic therapeutic effect of EXOs loaded with anti-PD-1 peptide on septic-ALI. METHODS: This study prepares a novel EXOs-based drug, named MEP, by engineering modification of HucMSCs-EXOs, which are non-immunogenic extracellular vesicles, loaded with anti-PD-1 peptide. The therapeutic effect and potential mechanism of MEP on septic-ALI are elucidated through in vivo and in vitro experiments, providing experimental evidence for the treatment of septic acute lung injury with MEP. RESULTS: We found that, compared to individual components (anti-PD-1 peptide or EXOs), MEP treatment can more effectively improve the lung injury index of septic-ALI mice, significantly reduce the expression levels of inflammatory markers CRP and PCT, as well as pro-inflammatory cytokines TNF-α and IL-1ß in serum, decrease lung cell apoptosis, and significantly increase the expression of anti-inflammatory cytokine IL-10 and CD68+ macrophages. In vitro, MEP co-culture promotes the proliferation of CD206+ macrophages, increases the M2/M1 macrophage ratio, and attenuates the inflammatory response. GEO data analysis and qRT-PCR validation show that MEP reduces the expression of inflammasome-related genes and M1 macrophage marker iNOS. CONCLUSION: In both in vitro and in vivo settings, MEP demonstrates superior therapeutic efficacy compared to individual components in the context of septic-ALI.

LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1.

Sepsis-induced acute lung injury is associated with lung epithelial cell injury. This study analyzed the role of the antimicrobial peptide LL37 with mitochondrial DNA (LL37-mtDNA) and its potential mechanism of action in lipopolysaccharide (LPS)-treated rat type II alveolar epithelial cells (RLE-6TN cells). RLE-6TN cells were treated with LPS alone or with LL37-mtDNA, followed by transcriptome sequencing. Differentially expressed and pivotal genes were screened using bioinformatics tools. The effects of LL37-mtDNA on cell viability, inflammation, apoptosis, reactive oxygen species (ROS) production, and autophagy-related hallmark expression were evaluated in LPS-treated RLE-6TN cells. Additionally, the effects of Hsp90aa1 silencing following LL37-mtDNA treatment were investigated in vitro. LL37-mtDNA further suppressed cell viability, augmented apoptosis, promoted the release of inflammatory cytokines, increased ROS production, and elevated LC3B expression in LPS-treated RLE-6TN cells. Using transcriptome sequencing and bioinformatics, ten candidate genes were identified, of which three core genes were verified to be upregulated in the LPS + LL37-mtDNA group. Additionally, Hsp90aa1 downregulation attenuated the effects of LL37-mtDNA on LPS-treated RLE-6TN cells. Hsp90aa1 silencing possibly acted as a crucial target to counteract the effects of LL37-mtDNA on viability, apoptosis, inflammation, and autophagy activation in LPS-treated RLE-6TN cells.