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Betacoronavirus , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Deficiência de Glucosefosfato Desidrogenase/sangue , Hemólise/efeitos dos fármacos , Metemoglobinemia/induzido quimicamente , Pneumonia Viral/tratamento farmacológico , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.
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Anticorpos Biespecíficos , Antineoplásicos , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Imunidade Humoral , Imunoglobulinas Intravenosas/uso terapêutico , Anticorpos Biespecíficos/uso terapêutico , Antígeno de Maturação de Linfócitos B/uso terapêutico , Antineoplásicos/uso terapêutico , Suplementos NutricionaisRESUMO
Organ failure is associated with increased mortality and morbidity in patients with systemic inflammatory response syndrome. Previously, we showed that a short course of infusion of a hydrogen sulfide (H(2)S) donor reduced metabolism with concurrent reduction of lung injury. Here, we hypothesize that prolonged H(2)S infusion is more protective than a short course in endotoxemia with organ failure. Also, as H(2)S has both pro- and anti-inflammatory effects, we explored the effect of H(2)S on interleukin production. Endotoxemia was induced by an intravenous bolus injection of LPS (7.5mg/kg) in mechanically ventilated rats. H(2)S donor NaHS (2mg/kg) or vehicle (saline) was infused and organ injury was determined after either 4 or 8h. A short course of H(2)S infusion was associated with reduction of lung and kidney injury. Prolonged infusion did not enhance protection. Systemically, infusion of H(2)S increased both the pro-inflammatory response during endotoxemia, as demonstrated by increased TNF-α levels, as well as the anti-inflammatory response, as demonstrated by increased IL-10 levels. In LPS-stimulated whole blood of healthy volunteers, co-incubation with H(2)S had solely anti-inflammatory effects, resulting in decreased TNF-α levels and increased IL-10 levels. Co-incubation with a neutralizing IL-10 antibody partly abrogated the decrease in TNF-α levels. In conclusion, a short course of H(2)S infusion reduced organ injury during endotoxemia, at least in part via upregulation of IL-10.
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Anti-Inflamatórios/metabolismo , Endotoxemia/tratamento farmacológico , Endotoxemia/patologia , Sulfeto de Hidrogênio/administração & dosagem , Sulfeto de Hidrogênio/uso terapêutico , Especificidade de Órgãos , Transdução de Sinais , Animais , Aspartato Aminotransferases/metabolismo , Biomarcadores/metabolismo , Gasometria , Temperatura Corporal/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar , Citocinas/sangue , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Humanos , Sulfeto de Hidrogênio/farmacologia , Infusões Intravenosas , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Cardiac surgery is frequently complicated by an acute vascular lung injury and this may be mediated, at least in part, by the (soluble) receptor for advanced glycation end products (sRAGE). METHODS: In two university hospital intensive care units, circulating sRAGE was measured together with the 68Gallium-transferrin pulmonary leak index (PLI), a measure of pulmonary vascular permeabiliy, in 60 consecutive cardiac surgery patients stratified by the amount of blood transfusion, within 3 hours of admission to the intensive care. RESULTS: Cardiac surgery resulted in elevated plasma sRAGE levels compared to baseline (315 ± 181 vs 110 ± 55 pg/ml, P = 0.001). In 37 patients the PLI was elevated 50% above normal. The PLI correlated with sRAGE (r2 = 0.11, P = 0.018). Plasma sRAGE discriminated well between those with an elevated PLI and those with a normal PLI (area under the operator curve 0.75; P = 0.035; 95% CI 0.55-0.95), with 91% sensitivity but low specificity of 36% at a cutoff value of 200 pg/mL. Blood transfusion did not influence sRAGE levels. CONCLUSIONS: sRAGE is elevated in plasma after cardiac surgery and indicates increased pulmonary vascular permeability. The level of sRAGE is not affected by transfusion.
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Lesão Pulmonar Aguda/sangue , Permeabilidade Capilar , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Receptores Imunológicos/metabolismo , Lesão Pulmonar Aguda/etiologia , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Transfusão de Sangue , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva , Pulmão/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Prospectivos , Curva ROC , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/sangueRESUMO
Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials.
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PURPOSE: Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post-CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy. METHODS: We performed a systematic review of phase II/III trials of US Food and Drug Administration-approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell-dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers. RESULTS: From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments. CONCLUSION: This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring.
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Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Cuidadores , Receptores de Antígenos de Linfócitos T , Pacientes Ambulatoriais , Terapia Baseada em Transplante de Células e TecidosRESUMO
The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020-May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.
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OBJECTIVE: To determine the effect of induced hypothermia on bacterial growth, lung injury, and mitochondrial function in a rat model of pneumococcal pneumosepsis. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Subjects were inoculated intratracheally with Streptococcus pneumoniae and controls received saline. After the development of pneumonia, mechanical ventilation was started with or without induced mild hypothermia (32 °C). Bacterial growth and inflammatory markers were determined in bronchoalveolar lavage fluid, blood, and organs. Oxidative phosphorylation and adenosine triphosphate contents were measured in mitochondria isolated from the liver and soleus muscle. MEASUREMENTS AND MAIN RESULTS: Inoculation with S. pneumoniae resulted in severe pneumonia with bacterial dissemination, distal organ injury, and blunted peripheral oxygen consumption on mechanical ventilation. Hypothermia did not affect bacterial growth in bronchoalveolar lavage fluid and in homogenized lungs compared with normothermic controls but was associated with reduced bacterial dissemination to the spleen with a trend toward reduced bacterial load in blood and liver. Hypothermia reduced lung injury, exemplified by reductions in pulmonary cell influx and bronchoalveolar lavage fluid protein levels compared with controls. Hypothermia reduced bronchoalveolar lavage fluid levels of interleukin-1ß, tended to reduce bronchoalveolar lavage fluid CINC-3 levels, but no effect was observed on bronchoalveolar lavage fluid tumor necrosis factor-α and interleukin-6 levels. Induced hypothermia restored the fall in oxygen consumption and adenosine triphosphate levels in the liver, whereas adenosine triphosphate/adenosine diphosphate ratios remained low. In muscle, induced hypothermia also reversed low oxygen consumption as a result of pneumonia, but with an increase in adenosine triphosphate levels, whereas adenosine triphosphate/adenosine diphosphate ratios were low. CONCLUSION: Hypothermia did not adversely affect bacterial growth, but rather reduced bacterial dissemination in a rat model of pneumococcal pneumosepsis. Furthermore, hypothermia reduced lung injury associated with restored adenosine triphosphate availability and turnover. These findings suggest that hypothermia may reduce organ injury by preventing sepsis-related mitochondrial dysfunction.
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Trifosfato de Adenosina/metabolismo , Hipotermia Induzida , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/prevenção & controle , Animais , Modelos Animais de Doenças , Masculino , Pneumonia Pneumocócica/microbiologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The innate immune response is important in ventilator-induced lung injury (VILI) but the exact pathways involved are not elucidated. The authors studied the role of the intracellular danger sensor NLRP3 inflammasome. METHODS: NLRP3 inflammasome gene expression was analyzed in respiratory epithelial cells and alveolar macrophages obtained from ventilated patients (n = 40). In addition, wild-type and NLRP3 inflammasome deficient mice were randomized to low tidal volume (approximately 7.5 ml/kg) and high tidal volume (approximately 15 ml/kg) ventilation. The presence of uric acid in lung lavage, activation of caspase-1, and NLRP3 inflammasome gene expression in lung tissue were investigated. Moreover, mice were pretreated with interleukin-1 receptor antagonist, glibenclamide, or vehicle before start of mechanical ventilation. VILI endpoints were relative lung weights, total protein in lavage fluid, neutrophil influx, and pulmonary and systemic cytokine and chemokine concentrations. Data represent mean ± SD. RESULTS: Mechanical ventilation up-regulated messenger RNA expression levels of NLRP3 in alveolar macrophages (1.0 ± 0 vs. 1.70 ± 1.65, P less than 0.05). In mice, mechanical ventilation increased both NLRP3 and apoptosis-associated speck-like protein messenger RNA levels, respectively (1.08 ± 0.55 vs. 3.98 ± 2.89; P less than 0.001 and 0.95 ± 0.53 vs. 6.0 ± 3.55; P less than 0.001), activated caspase-1, and increased uric acid levels (6.36 ± 1.85 vs. 41.9 ± 32.0, P less than 0.001). NLRP3 inflammasome deficient mice displayed less VILI due to high tidal volume mechanical ventilation compared with wild-type mice. Furthermore, treatment with interleukin-1 receptor antagonist or glibenclamide reduced VILI. CONCLUSIONS: Mechanical ventilation induced a NLRP3 inflammasome dependent pulmonary inflammatory response. NLRP3 inflammasome deficiency partially protected mice from VILI.
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Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Inflamassomos/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Caspase 1/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Ativação Enzimática/fisiologia , Células Epiteliais/metabolismo , Glibureto/farmacologia , Humanos , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Infiltração de Neutrófilos , Tamanho do Órgão/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Interleucina-1/antagonistas & inibidores , Respiração Artificial , Volume de Ventilação Pulmonar/fisiologia , Regulação para Cima/fisiologia , Ácido Úrico/metabolismoRESUMO
Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.
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Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Animais , Proteínas de Transporte/fisiologia , Proteínas de Choque Térmico/fisiologia , Humanos , Ácido Hialurônico/fisiologia , Imunidade Inata/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/fisiologia , Transdução de Sinais/fisiologia , Receptores Toll-Like/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologiaRESUMO
Severe respiratory syncytial virus (RSV) disease is a frequent cause of acute respiratory distress syndrome (ARDS) in young children, and is associated with marked lung epithelial injury and neutrophilic inflammation. Experimental studies on ARDS have shown that inhibition of apoptosis in the lungs reduces lung epithelial injury. However, the blockade of apoptosis in the lungs may also have deleterious effects by hampering viral clearance, and importantly, by enhancing or prolonging local proinflammatory responses. The aim of this study was to determine the effect of the broad caspase inhibitor Z-VAD(OMe)-FMK (zVAD) on inflammation and lung injury in a mouse pneumovirus model for severe RSV disease. Eight- to 11-week-old female C57BL/6OlaHsd mice were inoculated with the rodent-specific pneumovirus pneumonia virus of mice (PVM) strain J3666 and received multiple injections of zVAD or vehicle (control) during the course of disease, after which they were studied for markers of apoptosis, inflammation, and lung injury on day 7 after infection. PVM-infected mice that received zVAD had a strong increase in neutrophil numbers in the lungs, which was associated with decreased neutrophil apoptosis. Furthermore, zVAD treatment led to higher concentrations of several proinflammatory cytokines in the lungs and more weight loss in PVM-infected mice. In contrast, zVAD did not reduce apoptosis of lung epithelial cells and did not affect the degree of lung injury, permeability, and viral titers in PVM disease. We conclude that zVAD has an adverse effect in severe pneumovirus disease in mice by enhancing the lung proinflammatory response.
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BACKGROUND: Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses. We hypothesized that RAGE signaling contributes to the pro-inflammatory state induced by MV. METHODS: RAGE expression was analyzed in lung brush and lavage cells obtained from ventilated patients and lung tissue of ventilated mice. Healthy wild-type (WT) and RAGE knockout (KO) mice were ventilated with relatively low (approximately 7.5 ml/kg) or high (approximately 15 ml/kg) tidal volume. Positive end-expiratory pressure was set at 2 cm H2O during both MV strategies. Also, WT and RAGE KO mice with lipopolysaccharide (LPS)-induced lung injury were ventilated with the above described ventilation strategies. In separate experiments, the contribution of soluble RAGE, a RAGE isoform that may function as a decoy receptor, in ventilated RAGE KO mice was investigated. Lung wet-to-dry ratio, cell and neutrophil influx, cytokine and chemokine concentrations, total protein levels, soluble RAGE, and high-mobility group box 1 (HMGB1) presence in lung lavage fluid were analyzed. RESULTS: MV was associated with increased RAGE mRNA levels in both human lung brush samples and lung tissue of healthy mice. In healthy high tidal volume-ventilated mice, RAGE deficiency limited inflammatory cell influx. Other VILI parameters were not affected. In our second set of experiments where we compared RAGE KO and WT mice in a 2-hit model, we observed higher pulmonary cytokine and chemokine levels in RAGE KO mice undergoing LPS/high tidal volume MV as compared to WT mice. Third, in WT mice undergoing the LPS/high tidal volume MV, we observed HMGB1 presence in lung lavage fluid. Moreover, MV increased levels of soluble RAGE in lung lavage fluid, with the highest levels found in LPS/high tidal volume-ventilated mice. Administration of soluble RAGE to LPS/high tidal volume-ventilated RAGE KO mice attenuated the production of inflammatory mediators. CONCLUSIONS: RAGE was not a crucial contributor to the pro-inflammatory state induced by MV. However, the presence of sRAGE limited the production of pro-inflammatory mediators in our 2-hit model of LPS and high tidal volume MV.
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BACKGROUND: Bacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury. METHODS: Pulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT). In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated. RESULTS: S100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation. CONCLUSION: S100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4.
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Calgranulina A/metabolismo , Calgranulina B/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Animais , Líquido da Lavagem Broncoalveolar/química , Calgranulina B/efeitos adversos , Calgranulina B/genética , Humanos , Camundongos , Camundongos Knockout , Estatísticas não Paramétricas , Receptor 4 Toll-Like/genéticaRESUMO
Background. Mechanical ventilation (MV) has the potential to initiate ventilator-induced lung injury (VILI). The pathogenesis of VILI has been primarily studied in animal models using more or less injurious ventilator settings. However, we speculate that duration of MV also influences severity and character of VILI. Methods. Sixty-four healthy C57Bl/6 mice were mechanically ventilated for 5 or 12 hours, using lower tidal volumes with positive end-expiratory pressure (PEEP) or higher tidal volumes without PEEP. Fifteen nonventilated mice served as controls. Results. All animals remained hemodynamically stable and survived MV protocols. In both MV groups, PaO2 to FiO2 ratios were lower and alveolar cell counts were higher after 12 hours of MV compared to 5 hours. Alveolar-capillary permeability was increased after 12 hours compared to 5 hours, although differences did not reach statistical significance. Lung levels of inflammatory mediators did not further increase over time. Only in mice ventilated with increased strain, lung compliance declined and wet to dry ratio increased after 12 hours of MV compared to 5 hours. Conclusions. Deleterious effects of MV are partly dependent on its duration. Even lower tidal volumes with PEEP may initiate aspects of VILI after 12 hours of MV.
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Sepsis is characterized by a generalized inflammatory response and organ failure, associated with mitochondrial dysfunction. Hydrogen sulfide donor NaHS has anti-inflammatory properties, is able to reduce metabolism and can preserve mitochondrial morphology and function. Rats were challenged with live Streptococcus pneumonia or saline and infused with NaHS (36 µmol/kg/h) or vehicle. Lung and kidney injury markers were measured as well as mitochondrial function, viability and biogenesis. Infusion of NaHS reduced heart rate and body temperature, indicative of a hypo-metabolic state. NaHS infusion reduced sepsis-related lung and kidney injury, while host defense remained intact, as reflected by unchanged bacterial outgrowth. The reduction in organ injury was associated with a reversal of a fall in active oxidative phosphorylation with a concomitant decrease in ATP levels and ATP/ADP ratio. Preservation of mitochondrial respiration was associated with increased mitochondrial expression of α-tubulin and protein kinase C-ε, which acts as regulators of respiration. Mitochondrial damage was decreased by NaHS, as suggested by a reduction in mitochondrial DNA leakage in the lung. Also, NaHS treatment was associated with upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α, with a subsequent increase in transcription of mitochondrial respiratory subunits. These findings indicate that NaHS reduces organ injury in pneumosepsis, possibly via preservation of oxidative phosphorylation and thereby ATP synthesis as well as by promoting mitochondrial biogenesis. Further studies on the involvement of mitochondria in sepsis are required.