Necroptosis blockade prevents lung injury in severe influenza.

Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.

Polyphyllin B inhibited STAT3/NCOA4 pathway and restored gut microbiota to ameliorate lung tissue injury in cigarette smoke-induced mice.

OBJECTIVE: Smoking was a major risk factor for chronic obstructive pulmonary disease (COPD). This study plan to explore the mechanism of Polyphyllin B in lung injury induced by cigarette smoke (CSE) in COPD. METHODS: Network pharmacology and molecular docking were applied to analyze the potential binding targets for Polyphyllin B and COPD. Commercial unfiltered CSE and LPS were used to construct BEAS-2B cell injury in vitro and COPD mouse models in vivo, respectively, which were treated with Polyphyllin B or fecal microbiota transplantation (FMT). CCK8, LDH and calcein-AM were used to detect the cell proliferation, LDH level and labile iron pool. Lung histopathology, Fe3+ deposition and mitochondrial morphology were observed by hematoxylin-eosin, Prussian blue staining and transmission electron microscope, respectively. ELISA was used to measure inflammation and oxidative stress levels in cells and lung tissues. Immunohistochemistry and immunofluorescence were applied to analyze the 4-HNE, LC3 and Ferritin expression. RT-qPCR was used to detect the expression of FcRn, pIgR, STAT3 and NCOA4. Western blot was used to detect the expression of Ferritin, p-STAT3/STAT3, NCOA4, GPX4, TLR2, TLR4 and P65 proteins. 16S rRNA gene sequencing was applied to detect the gut microbiota. RESULTS: Polyphyllin B had a good binding affinity with STAT3 protein, which as a target gene in COPD. Polyphyllin B inhibited CS-induced oxidative stress, inflammation, mitochondrial damage, and ferritinophagy in COPD mice. 16S rRNA sequencing and FMT confirmed that Akkermansia and Escherichia_Shigella might be the potential microbiota for Polyphyllin B and FMT to improve CSE and LPS-induced COPD, which were exhausted by the antibiotics in C + L and C + L + P mice. CSE and LPS induced the decrease of cell viability and the ferritin and LC3 expression, and the increase of NCOA4 and p-STAT3 expression in BEAS-2B cells, which were inhibited by Polyphyllin B. Polyphyllin B promoted ferritin and LC3II/I expression, and inhibited p-STAT3 and NCOA4 expression in CSE + LPS-induced BEAS-2B cells. CONCLUSION: Polyphyllin B improved gut microbiota disorder and inhibited STAT3/NCOA4 pathway to ameliorate lung tissue injury in CSE and LPS-induced mice.

Role of neutrophil myeloperoxidase in the development and progression of high-altitude pulmonary edema.

BACKGROUND: Neutrophil infiltration and hypoxic pulmonary vasoconstriction induced by hypobaric hypoxic stress are vital in high-altitude pulmonary edema (HAPE). Myeloperoxidase (MPO), an important enzyme in neutrophils, is associated with inflammation and oxidative stress and is also involved in the regulation of nitric oxide synthase (NOS), an enzyme that catalyzes the production of the vasodilatory factor nitric oxide (NO). However, the role of neutrophil MPO in HAPE's progression is still uncertain. Therefore, we hypothesize that MPO is involved in the development of HAPE via NOS. METHODS: In Xining, China (altitude: 2260 m), C57BL/6 N wild-type and mpo-/- mice served as normoxic controls, while a hypobaric chamber simulated 7000 m altitude for hypoxia. L-NAME, a nitric oxide synthase (NOS) inhibitor to inhibit NO production, was the experimental drug, and D-NAME, without NOS inhibitory effects, was the control. After measuring pulmonary artery pressure (PAP), samples were collected and analyzed for blood neutrophils, oxidative stress, inflammation, vasoactive substances, pulmonary alveolar-capillary barrier permeability, and lung tissue morphology. RESULTS: Wild-type mice's lung injury scores, permeability, and neutrophil counts rose at 24 and 48 h of hypoxia exposure. Under hypoxia, PAP increased from 12.89 ± 1.51 mmHg under normoxia to 20.62 ± 3.33 mmHg significantly in wild-type mice and from 13.24 ± 0.79 mmHg to 16.50 ± 2.07 mmHg in mpo-/- mice. Consistent with PAP, inducible NOS activity, lung permeability, lung injury scores, oxidative stress response, and inflammation showed more significant increases in wild-type mice than in mpo-/- mice. Additionally, endothelial NOS activity and NO levels decreased more pronouncedly in wild-type mice than in mpo-/- mice. NOS inhibition during hypoxia led to more significant increases in PAP, permeability, and lung injury scores compared to the drug control group, especially in wild-type mice. CONCLUSION: MPO knockout reduces oxidative stress and inflammation to preserve alveolar-capillary barrier permeability and limits the decline in endothelial NOS activity to reduce PAP elevation during hypoxia. MPO inhibition emerges as a prospective therapeutic strategy for HAPE, offering avenues for precise interventions.

[Complications after conservative vs. operative treatment of severe thoracic trauma]. / Komplikationen nach operativer vs. konservativer Versorgung des schweren Thoraxtraumas.

BACKGROUND: Thoracic trauma is a frequent injury in the routine treatment of injured patients. Due to the increasing demographic changes a further increase is to be expected, especially after low-energy trauma. OBJECTIVE: Expected complications after conservative vs. operative treatment of various injury patterns of thoracic trauma. MATERIAL AND METHODS: Evaluation of a selective literature search regarding possible complications after thoracic trauma and formulation of instructions for action as expert recommendations. CONCLUSION: Both conservative and operative treatment of thoracic trauma have their specific complications, which have to be known to the treating physician. Lung contusions are often underestimated in the initial radiological diagnostics but often lead to relevant problems during the further course of treatment. After conservative treatment of rib fractures persistent pain, functional limitations or even relevant deformities due to secondary dislocation, can remain. There is a significant risk of overlooking or underestimating relevant injuries during the initial diagnostics which then leads to secondary complications. By far the most frequent risk of surgical treatment is an incorrect positioning of chest tubes. Overall, postoperative infections after chest trauma are relatively rare.

Fulminant sepsis secondary to severe lung contusion from the Lund University Cardiopulmonary Assist System device.

INTRODUCTION: Portable mechanical chest compression devices have been developed to improve upon many problems of manual compression, increase patient survival, and improve neurologic outcomes. However, the use of these devices is not without risk of harm to the patient. CASE REPORT: We describe a patient who received chest compressions from a mechanical compression device after cardiac arrest and subsequently developed fulminant sepsis secondary to lung contusions and a necrotizing pulmonary infection. DISCUSSION: Although injuries from the LUCAS have been reported, we believe this is the first reported fatal complication related to direct pulmonary injury from a mechanical compression device. CONCLUSION: More investigation is needed to determine the safety and efficacy of the LUCAS especially in obese patients.

Evolution of Pulmonary Contusions in Patients With Severe Rib Fractures: Cause for Concern?

INTRODUCTION: The progression of pulmonary contusions remains poorly understood. This study aimed to measure the radiographic change in pulmonary contusions over time and evaluate the association of the radiographic change with clinical outcomes and surgical stabilization of rib fractures (SSRF). METHODS: This retrospective cohort study included adults admitted with three or more displaced rib fractures or flail segment on trauma CT and when a chest CT was repeated within one week after trauma. Radiographic severity of pulmonary contusions was assessed using the Blunt Pulmonary Contusion Score (BPC18). Logistic regression was performed to evaluate the relation between SSRF and worsening contusions on repeat CT, adjusted for potential confounders. RESULTS: Of 231 patients, 56 (24%) had a repeat CT scan. Of these, 55 (98%) had pulmonary contusion on the first CT scan with a median BPC18 score of 5 (P25-P75 3-7). Repeat CTs showed an overall decrease of the median BPC18 score to 4 (P25-P75 2-6, P = .02), but demonstrated a worsening of the pulmonary contusion in 16 patients (29%). All repeat CTs conducted within 12 hours post-injury demonstrated increasing BPC18. Radiographic worsening of pulmonary contusions was not associated with SSRF, nor with worse respiratory outcomes or intensive care length of stay, compared to patients with radiographically stable or improving contusions. DISCUSSION: In patients with severe rib fracture patterns who undergo repeat imaging, pulmonary contusions are prevalent and become radiographically worse within at least the first 12 hours after injury. No association between radiographic worsening and clinical outcomes was found.

Lung Injury Prediction Model in Bone Marrow Transplantation: A Multicenter Cohort Study.

Rationale: Pulmonary complications contribute significantly to nonrelapse mortality following hematopoietic stem cell transplantation (HCT). Identifying patients at high risk can help enroll such patients into clinical studies to better understand, prevent, and treat posttransplantation respiratory failure syndromes. Objectives: To develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. Methods: Patients underwent HCT between January 1, 2019, and December 31, 2021, at one of three institutions. Those treated in Rochester, MN, formed the derivation cohort, and those treated in Scottsdale, AZ, or Jacksonville, FL, formed the validation cohort. The primary outcome was the development of acute respiratory distress syndrome (ARDS), with secondary outcomes including the need for invasive mechanical ventilation (IMV) and/or noninvasive ventilation (NIV). Predictors were based on prior case-control studies. Measurements and Main Results: Of 2,450 patients undergoing stem cell transplantation, there were 1,718 hospitalizations (888 patients) in the training cohort and 1,005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from prehospital predictors and 11 points from posttransplantation or early (<24-h) in-hospital predictors. The model performed well in predicting ARDS (C-statistic, 0.905; 95% confidence interval [CI], 0.870-0.941) and the need for IMV and/or NIV (C-statistic, 0.863; 95% CI, 0.828-0.898). The test cohort differed markedly in demographic, medical, and hematologic characteristics. The model also performed well in this setting in predicting ARDS (C-statistic, 0.841; 95% CI, 0.782-0.900) and the need for IMV and/or NIV (C-statistic, 0.872; 95% CI, 0.831-0.914). Conclusions: A novel prediction model incorporating data elements from the pretransplantation, posttransplantation, and early in-hospital domains can reliably predict the development of post-HCT acute respiratory failure.

Earthquake-related isolated blunt thoracic trauma patients: A special population study in the emergency department.

OBJECTIVE: The objective of this study is to compare patients with severe and mild blunt thoracic trauma, who survived an earthquake and presented to the emergency department (ED), in order to identify factors influencing the severity of trauma in earthquake-related thoracic injuries. METHODS: This retrospective, cross-sectional, observational comparative study included patients with isolated thoracic injuries due to the February 6th Kahramanmaras earthquake. The patients were categorized into severe and mild groups based on chest trauma scoring (CTS), and their characteristics were compared. RESULTS: The study included 53 patients, with 43 (88.1%) classified as having mild thoracic trauma and 10 (18.9%) classified as having severe thoracic trauma. There was no significant difference in the duration of entrapment between the groups (p = 0.824). The incidence of hemothorax, pneumothorax, rib fractures, and pneumomediastinum did not differ significantly between the two groups (p > 0.05). However, severe thoracic trauma was associated with a higher rate of lung contusion compared to the mild group (p = 0.045). The severe group exhibited significantly higher median scores for lung contusion, rib fractures, and total CTS compared to the mild group (p < 0.001). The mortality rate was significantly higher in the severe group (40%, n = 4) compared to the mild group (2.3%, n = 1) (p = 0.003). CONCLUSION: The duration of entrapment did not significantly affect the severity of thoracic injuries in earthquake-related blunt thoracic trauma. However, lung contusion was found to be a more prominent feature in these injuries compared to other clinical conditions such as hemothorax and pneumothorax. These findings highlight the distinct clinical implications of earthquake-related thoracic trauma and may have implications for management strategies in these cases.

Cord blood stem cell­derived Angptl7 ameliorates the severity of bronchopulmonary dysplasia via anti­inflammatory and proangiogenic effects.

Perinatal exposure of the neonatal lung to inflammation leads to decreased lung angiogenesis and the development of bronchopulmonary dysplasia (BPD). Notably, autologous cord blood mononuclear cells (ACBMNCs) can substantially prevent severe BPD and decrease the inflammatory response in surviving very preterm neonates. Angiopoietin­like protein 7 (Angptl7) is one of the main paracrine cytokines in cord blood stem cells, and is capable of stimulating human hematopoietic stem and progenitor cell expansion. The present study compared Angptl7 levels between the ACBMNCs infusion and control groups (cohort 1). Subsequently, the association between cord blood Angptl7 levels and BPD incidence in a cohort of very preterm neonates was assessed (cohort 2). The hypothesis was further verified in a lipopolysaccharide (LPS)­induced lung injury mouse model. The mRNA expression levels and protein concentrations of inflammatory cytokines in the lung tissue and mouse serum were measured using reverse transcription­quantitative PCR and ELISA, respectively. The number and diameter of lung vessels and macrophage infiltration were assessed using immunofluorescence staining. Compared with in the control group, Angptl7 levels were significantly higher in the ACBMNCs infusion group in cohort 1. In cohort 2, the cord blood Angptl7 levels were significantly lower in infants who later developed BPD. Multiple linear regression analysis showed that higher Angptl7 level was an independent protective factor for BPD. The concentrations of interleukin­6 and monocyte chemoattractant protein­1 were negatively correlated with cord blood Angptl7 level; whereas, vascular endothelial growth factor­A levels were positively correlated with Angptl7 levels. In the LPS­induced lung injury mouse model, the LPS group presented with a significant loss of pulmonary vessels and smaller vessel diameters, which were ameliorated in the Angptl7 treatment group. Furthermore, LPS­induced lung inflammation and macrophage infiltration were alleviated by Angptl7 treatment (P<0.05). In conclusion, the anti­inflammatory and proangiogenic effects of Angptl7 derived from cord blood stem cells may ameliorate BPD severity. The trial for cohort 1 was registered at ClinicalTrials.gov (trial registration no. NCT02999373; date registered, December 21, 2016).

Pyroptosis in septic lung injury: Interactions with other types of cell death.

Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of sepsis and one of the leading causes of patient death. Pyroptosis is a specific programmed cell death characterized by the release of inflammatory cytokines. Appropriate pyroptosis can reduce tissue damage and exert a protective effect against infection during sepsis. However, overactivated pyroptosis results in massive cell death, leading to septic shock, multiple organ dysfunction syndrome, and even an increased risk of secondary infection. Recent studies suggest that pyroptosis can interact with and cross-regulate other types of cell death programs to establish a complex network of cell death, which participates in the occurrence and development of septic lung injury. This review will focus on the interactions between pyroptosis and other types of cell death, including apoptosis, necroptosis, PANoptosis, NETosis, autophagy, and ferroptosis, to summarize the role of pyroptosis in sepsis-induced lung injury, and will discuss the potential therapeutic strategies of targeting pyroptosis during sepsis treatment.

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.

BACKGROUND: Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical, host-derived regulators of the microbiota. However, mechanisms that support microbiota homeostasis in response to inflammatory stimuli, such as supraphysiologic oxygen, remain unclear. RESULTS: We show that supraphysiologic oxygen exposure to neonatal mice, or direct exposure of intestinal organoids to supraphysiologic oxygen, suppresses the intestinal expression of AMPs and alters intestinal microbiota composition. Oral supplementation of the prototypical AMP lysozyme to hyperoxia-exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. CONCLUSIONS: Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury in newborns. Together, these data support that intestinal AMPs modulate lung injury and repair. Video Abstract.

Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.

Loss of microRNA-30a and sex-specific effects on the neonatal hyperoxic lung injury.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions. METHODS: Wild-type and miR-30a-/- neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a-/- mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a-/- male and female lung transcriptome data. RESULTS: Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a-/- mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a-/- female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a-/- female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium. CONCLUSIONS: miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.

Bronchopulmonary dysplasia (BPD) is a lung condition that affects babies born prematurely, causing problems with their lung development. Interestingly, BPD tends to affect boys more than girls, but we do not fully understand why. To investigate this, we conducted a study using mice. Female mice had better lung development and blood vessel formation when exposed to high oxygen levels. We found higher expression of a molecule called miR-30a in the female mice and seemed to be protective. So, we wanted to see if removing miR-30a would have the same effect on both male and female mice. To test this, we exposed newborn mice without miR-30a and normal mice to high oxygen levels or regular room air. Interestingly, the differences between normal males and females were no longer present in the mice without miR-30a. This suggested that miR-30a plays an important role in lung development. We also identified that the female mice without miR-30a, when exposed to high oxygen, had the greatest number of genes affected, and these gene changes were like those seen in blood samples from premature babies with BPD. Finally, we report that miR-30a was in a specific part of the lung called the bronchiolar epithelium. Overall, this study suggests that miR-30a is crucial in protecting premature lungs from damage caused by high oxygen levels. By understanding how miR-30a affects lung development, we may be able to develop new treatments for BPD in the future.

[Bilateral thoracic trauma-"double the trouble"?] / Beidseitiges Thoraxtrauma ­ "double the trouble"?

BACKGROUND: Thoracic trauma is associated with a high morbidity and mortality. Assessing the risk for complications is essential for planning the further treatment strategies and managing resources in thoracic trauma. OBJECTIVE: The aim of the study was to analyze concomitant injuries in unilateral and bilateral rib fractures and pulmonary contusions and evaluate differences in complication rates between the two. MATERIAL AND METHODS: In a retrospective study, data from all patients diagnosed with thoracic trauma at a level I trauma center were analyzed. Bivariate and multivariate analysis were used to examine an association of unilateral or bilateral rib fractures, serial rib fractures, and pulmonary contusions with multiple injuries and outcomes. In addition, multivariate regression analysis was utilized to determine the impact of age, gender and additional injuries on outcome. RESULTS: A total of 714 patients were included in the analysis. The mean Injury Severity Score (ISS) was 19. Patients with an additional thoracic spine injury had a significantly higher incidence of bilateral rib fractures. Pulmonary contusions were associated with younger age. Abdominal injuries were predictors for bilateral pulmonary contusions. Complications occurred in 36% of the patients. Bilateral injuries increased the complication rate up to 70%. Pelvic and abdominal injuries as well as the need for a chest drain were significant risk factors for complications. The mortality rate was 10%, with higher age, head and pelvic injuries as predictors. CONCLUSION: Patients with bilateral chest trauma had an increased incidence of complications and a higher mortality rate. Bilateral injuries and significant risk factors must therefore be considered. Injury of the thoracic spine should be excluded in those patients.

Periprocedural Complications With Balloon Pulmonary Angioplasty: Analysis of Global Studies.

BACKGROUND: Balloon pulmonary angioplasty (BPA) was introduced as a treatment modality for patients with inoperable, medically refractory chronic thromboembolic pulmonary hypertension decades ago; however, reports of high rates of pulmonary vascular injury have led to considerable refinement in procedural technique. OBJECTIVES: The authors sought to better understand the evolution of BPA procedure-related complications over time. METHODS: The authors conducted a systematic review of original articles published by pulmonary hypertension centers globally and performed a pooled cohort analysis of procedure-related outcomes with BPA. RESULTS: This systematic review identified 26 published articles from 18 countries worldwide from 2013 to 2022. A total of 1,714 patients underwent 7,561 total BPA procedures with an average follow up of 7.3 months. From the first period (2013-2017) to the second period (2018-2022), the cumulative incidence of hemoptysis/vascular injury decreased from 14.1% (474/3,351) to 7.7% (233/3,029) (P < 0.01); lung injury/reperfusion edema decreased from 11.3% (377/3,351) to 1.4% (57/3,943) (P < 0.01); invasive mechanical ventilation decreased from 0.7% (23/3,195) to 0.1% (4/3,062) (P < 0.01); and mortality decreased from 2.0% (13/636) to 0.8% (8/1,071) (P < 0.01). CONCLUSIONS: Procedure-related complications with BPA, including hemoptysis/vascular injury, lung injury/reperfusion edema, mechanical ventilation, and death, were less common in the second period (2018-2022), compared with first period (2013-2017), likely from refinement in patient and lesion selection and procedural technique over time.

PROTECTIVE EFFECTS OF HUMANIN-G IN HEMORRHAGIC SHOCK IN FEMALE MICE VIA AMPKα1-INDEPENDENT MECHANISMS.

ABSTRACT: Introduction: Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. We previously showed that the α1 subunit of AMP-activated protein kinase (AMPK), a crucial regulator of mitochondrial function, exerts a protective role in hemorrhagic shock. Humanin is a mitochondrial peptide with cytoprotective properties against cellular stress. Here, we investigated whether AMPKα1 influences systemic levels of endogenous humanin in hemorrhagic shock and whether treatment with the synthetic analog humanin-G affords beneficial effects. Methods: AMPKα1 wild-type (WT) and knockout (KO) female mice were subjected to hemorrhagic shock followed by resuscitation with blood and lactated Ringer's solution. In short-term studies, mice were treated with humanin-G or vehicle and sacrificed at 3 h after resuscitation; in survival studies, mice were treated with PEGylated humanin-G and monitored for 7 days. Results: Compared with the vehicle WT group, KO mice exhibited severe hypotension, cardiac mitochondrial damage, and higher plasma levels of Th17 cytokines but had similar lung injury and similar plasma elevation of endogenous humanin. Treatment with humanin-G improved lung injury, mean arterial blood pressure, and survival in both WT and KO mice, without affecting systemic cytokine or humanin levels. Humanin-G also ameliorated cardiac mitochondrial damage and increased adenosine triphosphate levels in KO mice. Beneficial effects of humanin-G were associated with lung cytoplasmic and nuclear activation of the signal transducer and activator of transcription-3 (STAT3) in AMPKα1-independent manner with marginal or no effects on mitochondrial STAT3 and complex I subunit GRIM-19. Conclusions: Our data indicate that circulating levels of humanin increase during hemorrhagic shock in AMPKα1-independent fashion as a defense mechanism to counteract metabolic derangement and that administration of humanin-G affords beneficial effects through STAT3 activation even in the absence of a functional AMPKα1.

Prediction of respiratory complications by quantifying lung contusion volume using chest computed tomography in patients with chest trauma.

Pulmonary contusion is an important risk factor for respiratory complications in trauma patients. Hence, we aimed to determine the relationship between the ratio of pulmonary contusion volume to the total lung volume and patient outcomes and the predictability of respiratory complications. We retrospectively included 73 patients with a pulmonary contusion on chest computed tomography (CT) from 800 patients with chest trauma admitted to our facility between January 2019 and January 2020. Chest injury severity was expressed as the ratio of pulmonary contusion volume to total lung volume by quantifying pulmonary contusion volume on chest CT. The cut-off value was 80%. Among the 73 patients with pulmonary contusion (77% males, mean age: 45.3 years), 28 patients had pneumonia, and five had acute respiratory distress syndrome. The number of patients in the severe risk group with > 20% of pulmonary contusion volume was 38, among whom 23 had pneumonia. For predicting pneumonia, the area under the receiver operating characteristic curves for the ratio of pulmonary contusion volume was 0.85 (95% confidence interval 0.76-0.95, p = 0.008); the optimal threshold was 70.4%. Quantifying pulmonary contusion volume using initial CT enables identifying patients with chest trauma at high risk of delayed respiratory complications.

A random forest model using flow cytometry data identifies pulmonary infection after thoracic injury.

BACKGROUND: Thoracic injury can cause impairment of lung function leading to respiratory complications such as pneumonia (PNA). There is increasing evidence that central memory T cells of the adaptive immune system play a key role in pulmonary immunity. We sought to explore whether assessment of cell phenotypes using flow cytometry (FCM) could be used to identify pulmonary infection after thoracic trauma. METHODS: We prospectively studied trauma patients with thoracic injuries who survived >48 hours at a Level 1 trauma center from 2014 to 2020. Clinical and FCM data from serum samples collected within 24 hours of admission were considered as potential variables. Random forest and logistic regression models were developed to estimate the risk of hospital-acquired and ventilator-associated PNA. Variables were selected using backwards elimination, and models were internally validated with leave-one-out. RESULTS: Seventy patients with thoracic injuries were included (median age, 35 years [interquartile range (IQR), 25.25-51 years]; 62.9% [44 of 70] male, 61.4% [42 of 70] blunt trauma). The most common injuries included rib fractures (52 of 70 [74.3%]) and pulmonary contusions (26 of 70 [37%]). The incidence of PNA was 14 of 70 (20%). Median Injury Severity Score was similar for patients with and without PNA (30.5 [IQR, 22.6-39.3] vs. 26.5 [IQR, 21.6-33.3]). The final random forest model selected three variables (Acute Physiology and Chronic Health Evaluation score, highest pulse rate in first 24 hours, and frequency of CD4 + central memory cells) that identified PNA with an area under the curve of 0.93, sensitivity of 0.91, and specificity of 0.88. A logistic regression with the same features had an area under the curve of 0.86, sensitivity of 0.76, and specificity of 0.85. CONCLUSION: Clinical and FCM data have diagnostic utility in the early identification of patients at risk of nosocomial PNA following thoracic injury. Signs of physiologic stress and lower frequency of central memory cells appear to be associated with higher rates of PNA after thoracic trauma. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level IV.

A review of 149 Divers Alert Network emergency call records involving diving minors.

INTRODUCTION: Minors have been scuba diving for decades, and while the initial concerns about potential long-term complications related to bone development appear to be unfounded, the incidence of scuba diving injuries among them has been poorly studied. METHODS: We reviewed 10,159 cases recorded in the DAN Medical Services call centre database from 2014 through 2016 and identified 149 cases of injured divers younger than 18 years. Records were analysed for case categorisation on the most common dive injuries. Information about demographics, level of training, risk factors, and relevant behavioural aspects were collected when available. RESULTS: While the most common reason for the call was to rule out decompression sickness, the majority of cases pertained to ear and sinus issues. However, 15% of the dive-related injuries involving minors had a final diagnosis of pulmonary barotrauma (PBt). While no reliable data is available on the incidence of PBt in adult divers, the authors' impression based on personal experience suggests that the number of cases of PBt in minors trends higher than in the general diving population. The narratives on some relevant records describe unmanageable levels of anxiety leading to panic. CONCLUSIONS: Based on the results and narratives on these cases, it is reasonable to infer that psychological immaturity, suboptimal management of adverse situations, and inadequate supervision might have led to severe injuries among these minor divers.

Misconnected chest tube: An extremely unusual fatal complication of secondary pneumothorax.

A rare and fatal complication of suction drainage of secondary spontaneous pneumothorax is reported. The patient, likely by a mistake, arbitrarily connected the oxygen supply tube to the thoracic drain. The sharp increase of intrapleural pressure combined with the atmospheric intraalveolar environment caused diffuse lung injury and cardiopulmonary collapse without a direct lung injury. The conflicting interests of patient autonomy and patient safety require further consideration.