Development of an Intelligent Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanoplatform for Enhanced Precise Therapy of Acute Lung Injury.

Introduction: Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) are commonly occurring devastating conditions that seriously threaten the respiratory system in critically ill patients. The current treatments improve oxygenation in patients with ALI/ARDS in the short term, but do not relieve the clinical mortality of patients with ARDS. Purpose: To develop the novel drug delivery systems that can enhance the therapeutic efficacy of ALI/ARDS and impede adverse effects of drugs. Methods: Based on the key pathophysiological process of ARDS that is the disruption of the pulmonary endothelial barrier, bilirubin (Br) and atorvastatin (As) were encapsulated into an intelligent reactive oxygen species (ROS)-responsive nanocarrier DSPE-TK-PEG (DPTP) to form nanoparticles (BA@DPTP) in which the thioketal bonds could be triggered by high ROS levels in the ALI tissues. Results: BA@DPTP could accumulate in inflammatory pulmonary sites through passive targeting strategy and intelligently release Br and As only in the inflammatory tissue via ROS-responsive bond, thereby enhancing the drugs effectiveness and markedly reducing side effects. BA@DPTP effectively inhibited NF-κB signaling and NLRP3/caspase-1/GSDMD-dependent pyroptosis in mouse pulmonary microvascular endothelial cells. BA@DPTP not only protected mice with lipopolysaccharide-induced ALI and retained the integrity of the pulmonary structure, but also reduced ALI-related mortality. Conclusion: This study combined existing drugs with nano-targeting strategies to develop a novel drug-targeting platform for the efficient treatment of ALI/ARDS.

Time-course transcriptome analysis of lungs from mice infected with inhaled aerosolized Stenotrophomonas maltophilia.

Background: Stenotrophomonas maltophilia (SMA) has emerged as an important pathogen capable of causing an opportunistic and nosocomial infection. We performed RNA sequencing (RNA-seq) of lung tissues from mice with pulmonary SMA infection over time via aerosolized intratracheal inhalation to investigate transcription profile changes in SMA-infected lungs. Methods: A mouse model of acute lethal SMA pneumonia was established in this study using aerosolized intratracheal inhalation, laying the groundwork for future SMA research. RNA-seq was then used to create a transcriptional profile of the lungs of the model mice at 0, 4, 12, 24, 48, and 72 hours post-infection (hpi). Mfuzz time clustering, weighted gene coexpression network analysis (WGCNA), and Immune Cell Abundance Identifier for mouse (ImmuCellAI-mouse) were used to analyze RNA-seq data. Results: A gradual change in the lung transcriptional profile was observed, which was consistent with the expected disease progression. At 4 hpi, the expression of genes related to the acute phase inflammatory response increased, as predicted abundance of innate immune cells. At this stage, an increased demand for energy was also observed, including an increase in the expression of genes involved in circulation, muscle function and mitochondrial respiratory chain function. The expression of genes associated with endoplasmic reticulum stress (ERS) and autophagy increased at 24 hpi. Unlike the number of natural killer (NK) cells following most bacterial lung infections, the abundance of NK cells decreased following infection with SMA. The expression levels of Cxcl10, Cd14, Gbp5, Cxcr2, Tnip1, Zc3h12a, Egr1, Sell and Gbp2 were high and previously unreported in SMA pneumonia, and they may be important targets for future studies. Conclusions: To our knowledge, this is the first study to investigate the pulmonary transcriptional response to SMA infection. The findings shed light on the molecular mechanisms underlying the pathogenesis of SMA pneumonia, which may aid in the development of therapies to reduce the occurrence of SMA pulmonary infection.

The impact of aspirin exposure prior to intensive care unit admission on the outcomes for patients with sepsis-associated acute respiratory failure.

Objectives: This present study aimed to infer the association between aspirin exposure prior to ICU admission and the clinical outcomes of patients with Sepsis-associated acute respiratory failure (S-ARF). Methods: We obtained data from the Medical Information Mart for Intensive Care IV 2.0. Patients were divided into pre-ICU aspirin exposure group and Non-aspirin exposure group based on whether they took aspirin before ICU admission. The primary outcome is 28-day mortality. Augmented inverse propensity weighted was used to explore the average treatment effect (ATE) of the pre-ICU aspirin exposure. A generalized additive mixed model was used to analyze the longitudinal data of neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), oxygenation index (P/F), dynamic lung compliance (Cdyn), mechanical power (MP), and mechanical power normalized to predicted body weight (WMP) in the two groups. A multiple mediation model was constructed to explore the possible mediators between pre-ICU aspirin exposure and outcomes of patients with S-ARF. Results: A total of 2090 S-ARF patients were included in this study. Pre-ICU aspirin exposure decreased 28-day mortality (ATE, -0.1945, 95% confidence interval [CI], -0.2786 to -0.1103, p < 0.001), 60-day mortality (ATE, -0.1781, 95% Cl, -0.2647 to -0.0915, p < 0.001), and hospital mortality (ATE, -0.1502, 95%CI, -0.2340 to -0.0664, p < 0.001). In subgroup analysis, the ATE for 28-day mortality, 60-day mortality, and hospital mortality were not statistically significant in the coronary care unit group, high-dose group (over 100 mg/d), and no invasive mechanical ventilation (IMV) group. After excluding these non-beneficiaries, Cdyn and P/F ratio of the pre-ICU aspirin exposure group increased by 0.31mL/cmH2O (SE, 0.21, p = 0.016), and 0.43 mmHg (SE, 0.24, p = 0.041) every hour compared to that of non-aspirin exposure group after initialing IMV. The time-weighted average of NLR, Cdyn, WMP played a mediating role of 8.6%, 24.7%, and 13% of the total effects of pre-ICU aspirin exposure and 28-day mortality, respectively. Conclusion: Pre-ICU aspirin exposure was associated with decreased 28-day mortality, 60-day mortality, and hospital mortality in S-ARF patients except those admitted to CCU, and those took a high-dose aspirin or did not receive IMV. The protective effect of aspirin may be mediated by a low dynamic level of NLR and a high dynamic level of Cdyn and WMP. The findings should be interpreted cautiously, given the sample size and potential for residual confounding.

Effects of mild hypothermia on expression of NF-E2-related factor 2 and heme-oxygenase-1 in cerebral cortex and hippocampus after cardiopulmonary resuscitation in rats.

OBJECTIVES: The aim of this study was to investigate the effects of mild hypothermia on expression of NF-E2-related factor 2 (Nrf2) and heme-oxygenase-1 (HO-1) of rat cerebral cortex and hippocampus after cardiopulmonary resuscitation and further investigate the possible mechanism of action. MATERIAL AND METHODS: To copy an asphyxia heart arrest model, Sprague Dawley rats were randomly divided into normothermia group, mild hypothermia group before restoration of spontaneous circulation (ROSC), and mild hypothermia group after ROSC. Body temperature in normothermia group was maintained at 37.5-39 °C, while in mild hypothermia group maintained at 32-34 °C by surface cooling with the ice pack. Each group then divided into three subgroups: 15 min, 30 min, and 60 min. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect the expression of Nrf2 and HO-1 mRNA in cerebral cortex and hippocampus. Hematoxylin-eosin (H&E) staining was performed to observe histological changes. Immunohistochemistry was performed to detect the expression of Nrf2 and HO-1 protein expression. RESULTS: The expression of Nrf2 and HO-1 in cerebral cortex and hippocampus after cardiopulmonary resuscitation (CPR) was significantly increased and mild hypothermia up regulated this level. HE staining showed that mild hypothermia significantly improved neuronal injury. CONCLUSION: Mild hypothermia has neuroprotective effects on cerebral ischemia/reperfusion injury after cardiac arrest. The possible mechanism is that Nrf2-ARE pathway in cerebral cortex and hippocampus after CPR is activated.