[Lung injury associated with vaping: A case report]. / Lesión pulmonar asociada al vapeo: informe de un caso.

Vaping is the practice of inhaling an aerosol created by heating a liquid with an electronic cigarette. These aerosols contain toxic, carcinogenic compounds and nicotine, an addictive substance. In Argentina, the commercialization of electronic cigarettes is prohibited. Acute lung injury associated with vaping (EVALI) is an acute respiratory disease that can be life threatening. An 18-year-old male patient, smoker, consulted for shortness of breath and fever. He presented with hypoxemic respiratory failure, and leukocytosis. The patient reported use of electronic cigarettes. Chest computed tomography (CT) showed extensive areas of ground glass opacities with areas of consolidation with air bronchogram. Antibiotic treatment was started and a fibrobronchoscopy was performed, which showed hematic debris, without endoluminal lesions. A diagnosis of EVALI was done and high doses systemic corticosteroids were prescribed. The patient evolved favorably, hewas discharged 48 hours after the end of treatment. In the control ambulatory CT was observed an improvement of the lesions. EVALI is an exclusion diagnosis, so it is necessary to rule out infectious diseases and pulmonary inflammatory processes. There are different scores that describe the probability of EVALI. The Centers for Disease Control and Prevention (CDC), developed in 2019 a definition of confirmed case based on vape exposure, imaging, clinical presentation and history. In 2019 was first reported an EVALI in Argentina. It is important to know the criteria for a confirmed case to initiate accurate and early treatment, considering the exponential increase in electronic cigarette use, mainly in the young population.

El vapeo es la práctica de inhalar un aerosol creado al calentar un líquido con cigarrillo electrónico. Estos aerosoles contienen tóxicos, compuestos cancerígenos y nicotina, sustancia adictiva. En nuestro país está prohibida la comercialización del cigarrillo electrónico. La lesión pulmonar aguda asociada al vapeo (EVALI) es una enfermedad respiratoria aguda potencialmente mortal. Se presenta el caso de un varón de 18 años, tabaquista, que consultó por falta de aire y fiebre. Presentaba insuficiencia respiratoria hipoxémica y leucocitosis, refiriendo reciente inicio de utilización de cigarrillo electrónico. En la tomografía computarizada de tórax (TC) se observaban extensas áreas en "vidrio esmerilado" bilaterales y áreas de consolidación con broncograma aéreo. Se inició tratamiento antibiótico y se realizó una fibrobroncoscopia que mostró restos hemáticos sin lesiones endoluminales. Se interpretó como EVALI y se indicaron corticoides sistémicos. El paciente evolucionó favorablemente y egresó a las 48 h de finalizado el tratamiento. En TC de control se observó mejoría de las lesiones. El diagnóstico de EVALI es de exclusión. Existen diferentes scores que describen la probabilidad de un EVALI. Los Centers for Disease Control and Prevention (CDC), propusieron en 2019 una definición de caso confirmado de EVALI basado en la exposición al vapeo, las imágenes, la presentación clínica y los antecedentes. La primera notificación de un caso de EVALI en la Argentina fue en el año 2019. Es importante conocer los criterios diagnósticos para poder iniciar un tratamiento preciso y precoz, considerando el aumento exponencial del uso de cigarrillo electrónico, principalmente en la población joven.

Acute lung injury is prevented by monocyte locomotion inhibitory factor in an experimental severe malaria mouse model.

Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of human lungs shows diffuse alveolar damage (DAD), the presence of CD8 lymphocytes, neutrophils, and increased expression of Intercellular Adhesion Molecule 1 (ICAM-1). P. berghei ANKA (PbA) infection in C57BL/6 mice reproduces many SM features, including acute lung injury characterized by DAD, CD8+ T lymphocytes and neutrophils in the lung parenchyma, and tissular expression of proinflammatory cytokines and adhesion molecules, such as IFNγ, TNFα, ICAM, and VCAM. Since this is related to a dysregulated immune response, immunomodulatory agents are proposed to reduce the complications of SM. The monocyte locomotion inhibitory factor (MLIF) is an immunomodulatory pentapeptide isolated from axenic cultures of Entamoeba hystolitica. Thus, we evaluated if the MLIF intraperitoneal (i.p.) treatment prevented SM-induced acute lung injury. The peptide prevented SM without a parasiticidal effect, indicating that its protective effect was related to modifications in the immune response. Furthermore, peripheral CD8+ leukocytes and neutrophil proportions were higher in infected treated mice. However, the treatment prevented DAD, CD8+ cell infiltration into the pulmonary tissue and downregulated IFNγ. Moreover, VCAM-1 expression was abrogated. These results indicate that the MLIF treatment downregulated adhesion molecule expression, impeding cell migration and proinflammatory cytokine tissular production, preventing acute lung injury induced by SM. Our findings represent a potential novel strategy to avoid this complication in various events where a dysregulated immune response triggers lung injury.

Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury.

The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1ß, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.

Anti-inflammatory and antioxidant properties of betaine protect against sepsis-induced acute lung injury: CT and histological evidence.

The aim of this research was to determine the anti-inflammatory effect of betaine on sepsis-induced acute respiratory distress syndrome (ARDS) in rats through histopathological examination, radiologic imaging, and biochemical analysis. Eight rats were included in the control group, and no procedure was performed. Feces intraperitoneal procedure (FIP) was performed on 24 rats to create a sepsis-induced ARDS model. These rats were separated into three groups as follows: FIP alone (sepsis group, n=8), FIP + saline (1 mL/kg, placebo group, n=8), and FIP + betaine (500 mg/kg, n=8). Computed tomography (CT) was performed after FIP, and the Hounsfield units (HU) value of the lungs was measured. The plasma levels of tumor necrosis factor (TNF)-α, interleukin-1ß (IL-1ß), IL-6, C-reactive protein, malondialdehyde (MDA), and lactic acid (LA) were determined, and arterial oxygen pressure (PaO2) and arterial CO2 pressure (PaCO2) were measured from an arterial blood sample. Histopathology was used to evaluate lung damage. This study completed all histopathological and biochemical evaluations in 3 months. All evaluated biomarkers were decreased in the FIP + betaine group compared to FIP + saline and FIP alone (all P<0.05). Also, the parenchymal density of the rat lung on CT and histopathological scores were increased in FIP + saline and FIP alone compared to control and these findings were reversed by betaine treatment (all P<0.05). Our study demonstrated that betaine suppressed the inflammation and ameliorated acute lung injury in a rat model of sepsis.

Ischemic Postconditioning Attenuates Myocardial Ischemia-Reperfusion-Induced Acute Lung Injury by Regulating Endoplasmic Reticulum Stress-Mediated Apoptosis.

OBJECTIVE: To explore the effect of ischemic postconditioning on myocardial ischemia-reperfusion-induced acute lung injury (ALI). METHODS: Forty adult male C57BL/6 mice were randomly divided into sham operation group (SO group), myocardial ischemia-reperfusion group (IR group), ischemic preconditioning group (IPRE group) and ischemic postconditioning group (IPOST group) (10 mice in each group). Anterior descending coronary artery was blocked for 60 min and then reperfused for 15 min to induce myocardial IR. For the IPRE group, 3 consecutive cycles of 5 min of occlusion and 5 minutes of reperfusion of the coronary arteries were performed before ischemia. For the IPOST group, 3 consecutive cycles of 5 min reperfusion and 5 minutes of occlusion of the coronary arteries were performed before reperfusion. Pathological changes of lung tissue, lung wet-to-dry (W/D) weight ratio, inflammatory factors, oxidative stress indicators, apoptosis of lung cells and endoplasmic reticulum stress (ERS) protein were used to evaluate lung injury. RESULTS: After myocardial IR, lung injury worsened significantly, manifested by alveolar congestion, hemorrhage, structural destruction of alveolar septal thickening, and interstitial neutrophil infiltration. In addition, lung W/D ratio was increased, plasma inflammatory factors, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17A, were increased, malondialdehyde (MDA) activity of lung tissue was increased, and superoxide dismutase (SOD) activity was decreased after myocardial IR. It was accompanied by the increased protein expression levels of ERS-related protein glucose regulatory protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and caspase-12, and the increased apoptotic indices of lung tissues. CONCLUSION: IPOST can effectively improve myocardial IR-induced ALI by inhibiting ERS-induced apoptosis of alveolar epithelial cells.

Spontaneous breathing promotes lung injury in an experimental model of alveolar collapse.

Vigorous spontaneous breathing has emerged as a promotor of lung damage in acute lung injury, an entity known as "patient self-inflicted lung injury". Mechanical ventilation may prevent this second injury by decreasing intrathoracic pressure swings and improving regional air distribution. Therefore, we aimed to determine the effects of spontaneous breathing during the early stage of acute respiratory failure on lung injury and determine whether early and late controlled mechanical ventilation may avoid or revert these harmful effects. A model of partial surfactant depletion and lung collapse was induced in eighteen intubated pigs of 32 ±4 kg. Then, animals were randomized to (1) SB-group: spontaneous breathing with very low levels of pressure support for the whole experiment (eight hours), (2) Early MV-group: controlled mechanical ventilation for eight hours, or (3) Late MV-group: first half of the experiment on spontaneous breathing (four hours) and the second half on controlled mechanical ventilation (four hours). Respiratory, hemodynamic, and electric impedance tomography data were collected. After the protocol, animals were euthanized, and lungs were extracted for histologic tissue analysis and cytokines quantification. SB-group presented larger esophageal pressure swings, progressive hypoxemia, lung injury, and more dorsal and inhomogeneous ventilation compared to the early MV-group. In the late MV-group switch to controlled mechanical ventilation improved the lung inhomogeneity and esophageal pressure swings but failed to prevent hypoxemia and lung injury. In a lung collapse model, spontaneous breathing is associated to large esophageal pressure swings and lung inhomogeneity, resulting in progressive hypoxemia and lung injury. Mechanical ventilation prevents these mechanisms of patient self-inflicted lung injury if applied early, before spontaneous breathing occurs, but not when applied late.

Liver-to-lung microembolic NETs promote gasdermin D-dependent inflammatory lung injury in sickle cell disease.

Acute lung injury, referred to as the acute chest syndrome, is a major cause of morbidity and mortality in patients with sickle cell disease (SCD), which often occurs in the setting of a vaso-occlusive painful crisis. P-selectin antibody therapy reduces hospitalization of patients with SCD by ∼50%, suggesting that an unknown P-selectin-independent mechanism promotes remaining vaso-occlusive events. In patients with SCD, intraerythrocytic polymerization of mutant hemoglobin promotes ischemia-reperfusion injury and hemolysis, which leads to the development of sterile inflammation. Using intravital microscopy in transgenic, humanized mice with SCD and in vitro studies with blood from patients with SCD, we reveal for the first time that the sterile inflammatory milieu in SCD promotes caspase-4/11-dependent activation of neutrophil-gasdermin D (GSDMD), which triggers P-selectin-independent shedding of neutrophil extracellular traps (NETs) in the liver. Remarkably, these NETs travel intravascularly from liver to lung, where they promote neutrophil-platelet aggregation and the development of acute lung injury. This study introduces a novel paradigm that liver-to-lung embolic translocation of NETs promotes pulmonary vascular vaso-occlusion and identifies a new GSDMD-mediated, P-selectin-independent mechanism of lung injury in SCD.

Dexmedetomidine Leads to the Mitigation of Myocardial Ischemia/Reperfusion-Induced Acute Lung Injury in Diabetic Rats Via Modulation of Hypoxia-Inducible Factor-1α.

INTRODUCTION: The objective of this study is to investigate the protective mechanism of dexmedetomidine (Dex) in myocardial ischemia/reperfusion (MIR)-induced acute lung injury (ALI) of diabetic rats by inhibiting hypoxia-inducible factor-1α (HIF-1α). METHODS: Initially, healthy male Sprague Dawley rats were treated with streptozocin to induce diabetes. Then, three weeks after the induction, Dex or lentiviral vector (LV)-HIF-1α was injected into the rats 30 minutes prior to the MIR modeling. After four weeks, lung tissues were harvested for pathological changes observation and the wet/dry weight (W/D) ratio determination. Afterwards, oxidative stress indicators and pro-inflammatory factors were measured. In addition, HIF-1α expression was assessed by immunohistochemistry and western blot analysis. RESULTS: Dex could suppress inflammatory cell infiltration, improve lung tissue structure, reduce pathological score and the W/D ratio, and block oxidative stress and inflammatory response in MIR-induced ALI of diabetic rats. Besides, Dex could also inhibit HIF-1α expression. Moreover, Dex + LV-HIF-1α reversed the protective role of Dex on diabetic MIR-induced ALI. CONCLUSION: Our study has made it clear that Dex inhibited the upregulation of HIF-1α in diabetic MIR-induced ALI, and thus protect lung functions by quenching the accumulation of oxygen radical and reducing lung inflammatory response.

Associations of high-mobility group box 1 and receptor for advanced glycation end products with acute lung injury in patient with acute aortic dissection.

OBJECTIVE: To investigate the associations of high-mobility group box 1 and its specific receptor, receptor for advanced glycation end products with acute lung injury in patients with acute aortic dissection. METHODS: A total of 96 acute aortic dissection patients were divided into acute aortic dissection with acute lung injury group (38 cases) and acute aortic dissection without acute lung injury group (58 cases), according to partial pressure of oxygen/fraction of inspired oxygen. In addition, 44 healthy individuals were selected for the control group. The blood samples were taken. The serum high-mobility group box 1 and receptor for advanced glycation end products levels were detected by enzyme-linked immunosorbent assay, and the partial pressure of oxygen/fraction of inspired oxygen was measured. RESULTS: 24 h after admission, the high-mobility group box 1 and receptor for advanced glycation end products levels in acute aortic dissection with acute lung injury and acute aortic dissection without acute lung injury groups were significantly higher than those in the control group, respectively (p<0.05), and each index in acute aortic dissection with acute lung injury group was significantly higher than that in acute aortic dissection without acute lung injury group (p<0.05). At each time point within 96 h after admission, compared with acute aortic dissection without acute lung injury group, in acute aortic dissection with acute lung injury group, the high-mobility group box 1 and receptor for advanced glycation end products levels were increased, respectively, and the partial pressure of oxygen/fraction of inspired oxygen was decreased. The correlation analysis showed that, in acute aortic dissection patients, the high-mobility group box 1 and receptor for advanced glycation end products levels were negatively correlated with partial pressure of oxygen/fraction of inspired oxygen, respectively (p<0.05). CONCLUSIONS: The serum high-mobility group box 1 and receptor for advanced glycation end products levels may be associated with the occurrence of acute lung injury in acute aortic dissection patients. Monitoring the high-mobility group box 1 and receptor for advanced glycation end products levels can evaluate the risk of acute aortic dissection with acute lung injury.

Associations of high-mobility group box 1 and receptor for advanced glycation end products with acute lung injury in patient with acute aortic dissection

SUMMARY OBJECTIVE: To investigate the associations of high-mobility group box 1 and its specific receptor, receptor for advanced glycation end products with acute lung injury in patients with acute aortic dissection. METHODS: A total of 96 acute aortic dissection patients were divided into acute aortic dissection with acute lung injury group (38 cases) and acute aortic dissection without acute lung injury group (58 cases), according to partial pressure of oxygen/fraction of inspired oxygen. In addition, 44 healthy individuals were selected for the control group. The blood samples were taken. The serum high-mobility group box 1 and receptor for advanced glycation end products levels were detected by enzyme-linked immunosorbent assay, and the partial pressure of oxygen/fraction of inspired oxygen was measured. RESULTS: 24 h after admission, the high-mobility group box 1 and receptor for advanced glycation end products levels in acute aortic dissection with acute lung injury and acute aortic dissection without acute lung injury groups were significantly higher than those in the control group, respectively (p<0.05), and each index in acute aortic dissection with acute lung injury group was significantly higher than that in acute aortic dissection without acute lung injury group (p<0.05). At each time point within 96 h after admission, compared with acute aortic dissection without acute lung injury group, in acute aortic dissection with acute lung injury group, the high-mobility group box 1 and receptor for advanced glycation end products levels were increased, respectively, and the partial pressure of oxygen/fraction of inspired oxygen was decreased. The correlation analysis showed that, in acute aortic dissection patients, the high-mobility group box 1 and receptor for advanced glycation end products levels were negatively correlated with partial pressure of oxygen/fraction of inspired oxygen, respectively (p<0.05). CONCLUSIONS: The serum high-mobility group box 1 and receptor for advanced glycation end products levels may be associated with the occurrence of acute lung injury in acute aortic dissection patients. Monitoring the high-mobility group box 1 and receptor for advanced glycation end products levels can evaluate the risk of acute aortic dissection with acute lung injury.

Global Trends in Research of Macrophages Associated With Acute Lung Injury Over Past 10 Years: A Bibliometric Analysis.

Acute lung injury (ALI) is an intractable disorder associated with macrophages. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers about macrophages in ALI over the past 10 years. We retrieved publications published from 2011 to 2020 and their recorded information from Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). Bibliometrix package was used to analyze bibliometric indicators, and the VOSviewer was used to visualize the trend and hotspots of researches on macrophages in ALI. Altogether, 2,632 original articles were reviewed, and the results showed that the annual number of publications (Np) concerning the role of macrophages in ALI kept increasing over the past 10 years. China produced the most papers, the number of citations (Nc) and H-index of the USA ranked first. Shanghai Jiaotong University and INT IMMUNOPHARMACOL were the most prolific affiliation and journal, respectively. Papers published by Matute-Bello G in 2011 had the highest local citation score (LCS). Recently, the keywords "NLRP3" and "extracellular vesicles" appeared most frequently. Besides, researches on COVID-19-induced ALI related to macrophages seemed to be the hotspot recently. This bibliometric study revealed that publications related to macrophages in ALI tend to increase continuously. China was a big producer and the USA was an influential country in this field. Most studies were mainly centered on basic researches in the past decade, and pathways associated with the regulatory role of macrophages in inhibiting and attenuating ALI have become the focus of attention in more recent studies. What is more, our bibliometric analysis showed that macrophages play an important role in COVID-19-induced ALI and may be a target for the treatment of COVID-19.

Melatonin can be, more effective than N-acetylcysteine, protecting acute lung injury induced by intestinal ischemia-reperfusion in rat model.

OBJECTIVES: The current study compared the impact of pretreatment with melatonin and N-acetylcysteine (NAC) on the prevention of rat lung damage following intestinal ischemia-reperfusion (iIR). METHODS: Twenty-eight Wistar rats were subjected to intestinal ischemia induced by a 60 min occlusion of the superior mesenteric artery, followed by reperfusion for 120 min. Animals were divided into the following groups (n=7 per group): sham, only abdominal incision; SS+iIR, pretreated with saline solution and iIR; NAC+iIR, pretreated with NAC (20 mg/kg) and iIR; MEL+iIR, pretreated with melatonin (20 mg/kg) and iIR. Oxidative stress and inflammatory mediators were measured and histological analyses were performed in the lung tissues. RESULTS: Data showed a reduction in malondialdehyde (MDA), myeloperoxidase (MPO), and TNF-alpha in the animals pretreated with NAC or MEL when compared to those treated with SS+iIR (p<0.05). An increase in superoxide dismutase (SOD) levels in the NAC- and MEL-pretreated animals as compared to the SS+iIR group (34±8 U/g of tissue; p<0.05) was also observed. TNF-α levels were lower in the MEL+iIR group (91±5 pg/mL) than in the NAC+iIR group (101±6 pg/mL). Histological analysis demonstrated a higher lung lesion score in the SS+iIR group than in the pretreated groups. CONCLUSION: Both agents individually provided tissue protective effect against intestinal IR-induced lung injury, but melatonin was more effective in ameliorating the parameters analyzed in this study.

Green propolis extract attenuates acute kidney injury and lung injury in a rat model of sepsis.

Sepsis is the leading cause of acute kidney injury (AKI) and lung injury worldwide. Despite therapeutic advances, sepsis continues to be associated with high mortality. Because Brazilian green propolis (GP) has promising anti-inflammatory, antioxidant, and immunomodulatory properties, we hypothesized that it would protect kidneys and lungs in rats induced to sepsis by cecal ligation and puncture (CLP). Male Wistar rats were divided into groups-control (sham-operated); CLP (CLP only); and CLP + GP (CLP and treatment with GP at 6 h thereafter)-all receiving volume expansion and antibiotic therapy at 6 h after the procedures. By 24 h after the procedures, treatment with GP improved survival, attenuated sepsis-induced AKI, and restored renal tubular function. Whole-blood levels of reduced glutathione were higher in the CLP + GP group. Sepsis upregulated the Toll-like receptor 4/nuclear factor-kappa B axis in lung and renal tissues, as well as increasing inflammatory cytokine levels and macrophage infiltration; all of those effects were attenuated by GP. Treatment with GP decreased the numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in renal and lung tissue, as well as protecting the morphology of the renal mitochondria. Our data open the prospect for clinical trials of the use of GP in sepsis.

Melatonin can be, more effective than N-acetylcysteine, protecting acute lung injury induced by intestinal ischemia-reperfusion in rat model

OBJECTIVES: The current study compared the impact of pretreatment with melatonin and N-acetylcysteine (NAC) on the prevention of rat lung damage following intestinal ischemia-reperfusion (iIR). METHODS: Twenty-eight Wistar rats were subjected to intestinal ischemia induced by a 60 min occlusion of the superior mesenteric artery, followed by reperfusion for 120 min. Animals were divided into the following groups (n=7 per group): sham, only abdominal incision; SS+iIR, pretreated with saline solution and iIR; NAC+iIR, pretreated with NAC (20 mg/kg) and iIR; MEL+iIR, pretreated with melatonin (20 mg/kg) and iIR. Oxidative stress and inflammatory mediators were measured and histological analyses were performed in the lung tissues. RESULTS: Data showed a reduction in malondialdehyde (MDA), myeloperoxidase (MPO), and TNF-alpha in the animals pretreated with NAC or MEL when compared to those treated with SS+iIR (p<0.05). An increase in superoxide dismutase (SOD) levels in the NAC- and MEL-pretreated animals as compared to the SS+iIR group (34±8 U/g of tissue; p<0.05) was also observed. TNF-α levels were lower in the MEL+iIR group (91±5 pg/mL) than in the NAC+iIR group (101±6 pg/mL). Histological analysis demonstrated a higher lung lesion score in the SS+iIR group than in the pretreated groups. CONCLUSION: Both agents individually provided tissue protective effect against intestinal IR-induced lung injury, but melatonin was more effective in ameliorating the parameters analyzed in this study.

Prenatal programming of the immune response induced by maternal periodontitis: Effects on the development of acute lung injury in rat pups.

AIMS: Oral cavity pathogens play an important systemic role, modulating the development of several diseases. Periodontitis is a very common oral disease associated with dental biofilm. It is characterized by gum inflammation, periodontal ligament degeneration, dental cementum and alveolar bone loss. Studies point to the association between maternal periodontitis and adverse outcomes during pregnancy. However, they did not evaluate the impact of maternal periodontitis in the offspring. Thus, our objective was to investigate the effects of maternal periodontitis in the immune system of offspring. MATERIAL AND METHODS: For this evaluation we induced acute lung injury in rat pups. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after the birth, offspring was submitted to acute lung inflammation by administration of lipopolysaccharide (LPS, Salmonella abortus equi, 5 mg/kg, ip). KEY FINDINGS: Our results showed that maternal periodontitis increased myeloperoxidase activity, the levels of TNF-alpha and IL-17A in the bronchoalveolar fluid, the gene expression of TNF-alpha, IL-17A, and cyclooxygenases 1 and 2. In addition, maternal periodontitis did not alter the number of leukocytes migrated into the lung, tracheal responsiveness, expression of TLR4 and NF-KB translocation. SIGNIFICANCE: This study showed prenatal programming of the immune response induced by maternal periodontitis, and reinforces the importance of oral health care during pregnancy.

Haem oxygenase protects against thrombocytopaenia and malaria-associated lung injury.

BACKGROUND: Malaria-triggered lung injury can occur in both severe and non-severe cases. Platelets may interact with parasitized erythrocytes, leukocytes and endothelium. These interactions can lead to microvessel obstructions and induce release of inflammatory mediators. Induction of the haem oxygenase enzyme is important in the host's response to free haem and to several other molecules generated by infectious or non-infectious diseases. In addition, an important role for the haem oxygenase-1 isotype has been demonstrated in experimental cerebral malaria and in clinical cases. Therefore, the present work aims to determine the influence of haem oxygenase in thrombocytopaenia and acute pulmonary injury during infection with Plasmodium berghei strain NK65. METHODS: C57BL/6 mice were infected with P. berghei and analysed 7-10 days post-infection. For each experiment, Cobalt Protoporphyrin IX/CoPPIX or saline were administered. Bronchoalveolar lavage fluid was used for total and differential leukocyte count and for protein measurement. Lungs were used for histological analyses or for analysis of cytokines and western blotting. The lung permeability was analysed by Evans blue dye concentration. Platelet-leukocyte aggregate formation was assayed using the flow cytometer. RESULTS: Plasmodium berghei NK65 infection generated an intense lung injury, with increased levels of inflammatory mediators, oedema, and cell migration into the lung. Plasmodium berghei infection was also accompanied by marked thrombocytopaenia and formation of platelet-leukocyte aggregates in peripheral blood. Treatment with the HO-1 inducer cobalt protoporphyrin IX (CoPPIX) modified the inflammatory response but did not affect the evolution of parasitaemia. Animals treated with CoPPIX showed an improvement in lung injury, with decreased inflammatory infiltrate in the lung parenchyma, oedema and reduced thrombocytopaenia. CONCLUSION: Data here presented suggest that treatment with CoPPIX inducer leads to less severe pulmonary lung injury and thrombocytopaenia during malaria infection, thus increasing animal survival.

Glycogen synthase kinase-3 beta inhibitors protectagainst the acute lung injuries resulting from acute necrotizing pancreatitis.

PURPOSE: The research is intended for clarification of the efficacy as well as the underlying mechanism of GSK-3ß inhibitors on the advancement of acute lung injuries in acute necrotizing pancreatitis (ANP) in rats. METHODS: Seventy-two rats were randomly divided into 6 groups: (1)ANP-vehicle; (2)ANP-TDZD-8;(3)ANP-SB216763;(4)Sham-vehicle;(5)Sham-TDZD-8;(6)Sham-SB216763; Blood biochemical test, histopathological examination and immunohistochemical analysis of rats pancreas and lung tissues were performed. The protein expression of GSK-3ß, phospho-GSK-3ß (Ser9), iNOS, ICAM-1, TNF-α, and IL-10 were detected in lung tissues by Western-blot. RESULTS: The outcomes revealed that the intervention of GSK-3ß inhibitors alleviated the pathological damage of pancreas and lung (P<0.01), reduced serum amylase, lipase, hydrothorax and lung Wet-to-Dry Ratio, attenuated serum concentrations of IL-1ß and IL-6 (P<0.01), inhibited the activation of NF-κB, and abated expression of iNOS, ICAM-1 and TNF-α protein, but up-regulated IL-10 expression in lung of ANP rats (P<0.01). The inflammatory response and various indicators in ANP-TDZD-8 groups were lower than those in ANP-SB216763 groups. CONCLUSIONS: Inhibition of GSK-3ß weakens acute lung injury related to ANP via the inhibitory function of NF-κB signaling pathway. Different kinds of GSK-3ß inhibitors have different effects to ANP acute lung injury.

Effects of Obesity on Pulmonary Inflammation and Remodeling in Experimental Moderate Acute Lung Injury.

Obese patients are at higher risk of developing acute respiratory distress syndrome (ARDS); however, their survival rates are also higher compared to those of similarly ill non-obese patients. We hypothesized that obesity would not only prevent lung inflammation, but also reduce remodeling in moderate endotoxin-induced acute lung injury (ALI). Obesity was induced by early postnatal overfeeding in Wistar rats in which the litter size was reduced to 3 pups/litter (Obese, n = 18); Control animals (n = 18) were obtained from unculled litters. On postnatal day 150, Control, and Obese animals randomly received E. coli lipopolysaccharide (ALI) or saline (SAL) intratracheally. After 24 h, echocardiography, lung function and morphometry, and biological markers in lung tissue were evaluated. Additionally, mediator expression in neutrophils and macrophages obtained from blood and bronchoalveolar lavage fluid (BALF) was analyzed. Compared to Control-SAL animals, Control-ALI rats showed no changes in echocardiographic parameters, increased lung elastance and resistance, higher monocyte phagocytic capacity, collagen fiber content, myeloperoxidase (MPO) activity, and levels of interleukin (IL-6), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, and type III (PCIII), and I (PCI) procollagen in lung tissue, as well as increased expressions of TNF-α and monocyte chemoattractant protein (MCP)-1 in blood and BALF neutrophils. Monocyte (blood) and macrophage (adipose tissue) phagocytic capacities were lower in Obese-ALI compared to Control-ALI animals, and Obese animals exhibited reduced neutrophil migration compared to Control. Obese-ALI animals, compared to Obese-SAL, exhibited increased interventricular septum thickness (p = 0.003) and posterior wall thickness (p = 0.003) and decreased pulmonary acceleration time to pulmonary ejection time ratio (p = 0.005); no changes in lung mechanics, IL-6, TNF-α, TGF-ß, PCIII, and PCI in lung tissue; increased IL-10 levels in lung homogenate (p = 0.007); reduced MCP-1 expression in blood neutrophils (p = 0.009); decreased TNF-α expression in blood (p = 0.02) and BALF (p = 0.008) neutrophils; and increased IL-10 expression in monocytes (p = 0.004). In conclusion, after endotoxin challenge, obese rats showed less deterioration of lung function, secondary to anti-inflammatory and anti-fibrotic effects, as well as changes in neutrophil and monocyte/macrophage phenotype in blood and BALF compared to Control rats.

Low-power laser alters mRNA levels from DNA repair genes in acute lung injury induced by sepsis in Wistar rats.

Acute lung injury (ALI) is defined as respiratory failure syndrome, in which the pathogenesis could occur from sepsis making it a life-threatening disease by uncontrolled hyperinflammatory responses. A possible treatment for ALI is the use of low-power infrared lasers (LPIL), whose therapeutical effects depend on wavelength, power, fluence, and emission mode. The evaluation mRNA levels of repair gene related to oxidative damage after exposure to LPIL could provide important information about the modulation of genes as treatment for ALI. Thus, the aim of this study was to evaluate the mRNA levels from OGG1, APEX1, ERCC2, and ERCC1 genes in lung tissue from Wistar rats affected by ALI and after exposure to LPIL (808 nm; 100 mW). Adult male Wistar rats (n = 30) were randomized into six groups (n = 5, for each group): control, 10 J/cm2 (2 J), 20 J/cm2 (5 J), ALI, ALI + LPIL 10 J/cm2 and ALI + LPIL 20 J/cm2. ALI was induced by intraperitoneal E. coli lipopolysaccharide injection (10 mg/kg). Lungs were removed, and samples were withdrawn for total RNA extraction, cDNA synthesis, and mRNA levels were evaluated by RT-qPCR. Data normality was verified by Kolmogorov-Smirnov, comparisons among groups were by Student's t test, Mann-Whitney test, one-way ANOVA, Kruskal-Wallis followed by post-tests. Data showed that OGG1 (0.39 ± 0.10), ERCC2 (0.67 ± 0.24), and ERCC1 (0.60 ± 0.19) mRNA levels are reduced in ALI group when compared with the control group (1.00 ± 0.07, 1.03 ± 0.25, 1.01 ± 0.16, respectively) and, after LPIL, mRNA relative levels from DNA repair genes are altered when compared to non-exposed ALI group. Our research shows that ALI alter mRNA levels from genes related to base and nucleotide excision repair genes, suggesting that DNA repair is part of cell response to sepsis, and that photobiomodulation could modulate the mRNA levels from these genes in lung tissue.

Photobiomodulation modulates the resolution of inflammation during acute lung injury induced by sepsis.

Sepsis is a big health problem and one of the most common causes of acute lung injury (ALI) leading to high mortality. Pro-resolving mediators play an important role in abrogating the inflammation and promoting tissue homeostasis restoration. ALI treatment is still a clinical health problem, so new therapies are needed. Here, we evaluated the effect of photobiomodulation treatment on the resolution process of ALI induced by lipopolysaccharide (LPS). Male Balb/c mice were submitted to LPS (ip) or vehicle and irradiated or not with light emitting diode (LED) 2 and 6 h after LPS or vehicle injection, and the parameters were investigated 3 and 7 days after the injections. Our results showed that after 3 days of LED treatment the blood and bronchoalveolar lavage (BAL) cells as well as interleukins (IL) including IL-6 and IL-17 were reduced. No differences were observed in the bone marrow cells, tracheal reactivity, and lipoxin A4 and resolvin E2. Indeed, after 7 days of LED treatment the bone marrow cells, lymphocytes, and lipoxin A4 were increased, while IL-6, IL-17, and IL-10 were decreased. No differences were observed in the blood cells and tracheal reactivity. Thus, our results showed that LED treatment attenuated ALI induced by sepsis by modulating the cell mobilization from their reserve compartments. In addition, we also showed later effects of the LED up to 7 days after the treatment. This study proposes photobiomodulation as therapeutic adjuvant to treat ALI.