Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD.

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

Mitochondria in health, disease, and aging.

Mitochondria are well known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. Although oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.

Association of body mass index with morbidity in patients hospitalised with COVID-19.

PURPOSE: To evaluate the association between body mass index (BMI) and clinical outcomes other than death in patients hospitalised and intubated with COVID-19. METHODS: This is a single-centre cohort study of adults with COVID-19 admitted to New York Presbyterian Hospital-Weill Cornell Medicine from 3 March 2020 through 15 May 2020. Baseline and outcome variables, as well as lab and ventilatory parameters, were generated for the admitted and intubated cohorts after stratifying by BMI category. Linear regression models were used for continuous, and logistic regression models were used for categorical outcomes. RESULTS: The study included 1337 admitted patients with a subset of 407 intubated patients. Among admitted patients, hospital length of stay (LOS) and home discharge was not significantly different across BMI categories independent of demographic characteristics and comorbidities. In the intubated cohort, there was no difference in in-hospital events and treatments, including renal replacement therapy, neuromuscular blockade and prone positioning. Ventilatory ratio was higher with increasing BMI on days 1, 3 and 7. There was no significant difference in ventilator free days (VFD) at 28 or 60 days, need for tracheostomy, hospital LOS, and discharge disposition based on BMI in the intubated cohort after adjustment. CONCLUSIONS: In our COVID-19 population, there was no association between obesity and morbidity outcomes, such as hospital LOS, home discharge or VFD. Further research is needed to clarify the mechanisms underlying the reported effects of BMI on outcomes, which may be population dependent.

Effect of Neonatal Treatment With the NMDA Receptor Antagonist, MK-801, During Different Temporal Windows of Postnatal Period in Adult Prefrontal Cortical and Hippocampal Function.

The neonatal MK-801 model of schizophrenia has been developed based on the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia. This animal model is generated with the use of the NMDA receptor antagonist, MK-801, during different temporal windows of postnatal life of rodents leading to behavioral defects in adulthood. However, no studies have examined the role of specific postnatal time periods in the neonatal MK-801 (nMK-801) rodent model and the resulting behavioral and neurobiological effects. Thus, the goal of this study is to systematically investigate the role of NMDA hypofunction, during specific temporal windows in postnatal life on different cognitive and social behavioral paradigms, as well as various neurobiological effects during adulthood. Both female and male mice were injected intraperitoneally (i.p.) with MK-801 during postnatal days 7-14 (p7-14) or 11-15 (p11-15). Control mice were injected with saline during the respective time period. In adulthood, mice were tested in various cognitive and social behavioral tasks. Mice nMK-801-treated on p7-14 show impaired performance in the novel object, object-to-place, and temporal order object recognition (TOR) tasks, the sociability test, and contextual fear extinction. Mice nMK-801-treated on p11-15 only affects performance in the TOR task, the social memory test, and contextual fear extinction. No differences were identified in the expression of NMDA receptor subunits, the synapsin or PSD-95 proteins, either in the prefrontal cortex (PFC) or the hippocampus (HPC), brain regions significantly affected in schizophrenia. The number of parvalbumin (PV)-expressing cells is significantly reduced in the PFC, but not in the HPC, of nMK-801-treated mice on p7-14 compared to their controls. No differences in PV-expressing cells (PFC or HPC) were identified in nMK-801-treated mice on p11-15. We further examined PFC function by recording spontaneous activity in a solution that allows up state generation. We find that the frequency of up states is significantly reduced in both nMK-801-treated mice on p7-14 and p11-15 compared to saline-treated mice. Furthermore, we find adaptations in the gamma and high gamma activity in nMK-801-treated mice. In conclusion, our results show that MK-801 treatment during specific postnatal temporal windows has differential effects on cognitive and social behaviors, as well as on underlying neurobiological substrates.

Evaluation of Albumin Kinetics in Critically Ill Patients With Coronavirus Disease 2019 Compared to Those With Sepsis-Induced Acute Respiratory Distress Syndrome.

OBJECTIVES: This report aims to characterize the kinetics of serum albumin in critically ill patients with coronavirus disease 2019 compared with critically ill patients with sepsis-induced acute respiratory distress syndrome. DESIGN: Retrospective analysis. SETTING: We analyzed two critically ill cohorts, one with coronavirus disease 2019 and another with sepsis-induced acute respiratory distress syndrome, treated in the New York Presbyterian Hospital-Weill Cornell Medical Center. PATIENTS: Adult patients in the coronavirus disease 2019 cohort, diagnosed through reverse transcriptase-polymerase chain reaction assays performed on nasopharyngeal swabs, were admitted from March 3, 2020, to July 10, 2020. Adult patients in the sepsis-induced acute respiratory distress syndrome cohort, defined by Sepsis III criteria receipt of invasive mechanical ventilation and a Pao2/Fio2 ratio less than 300 were admitted from December 12, 2006, to February 26, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated serial serum albumin levels within 30 days after ICU admission in each cohort. We then examined the albumin progression trajectories, aligned at ICU admission time to test the relationship at a similar point in disease progression, in survivors and nonsurvivors. Albumin trajectory in all critically ill coronavirus disease 2019 patients show two distinct phases: phase I (deterioration) showing rapid albumin loss and phase II (recovery) showing albumin stabilization or improvement. Meanwhile, albumin recovery predicted clinical improvement in critical coronavirus disease 2019. In addition, we found a deterioration and recovery trends in survivors in the sepsis-induced acute respiratory distress syndrome cohort but did not find such two-phase trend in nonsurvivors. CONCLUSIONS: The changes in albumin associated with coronavirus disease 2019 associated respiratory failure are transient compared with sepsis-associated acute respiratory distress syndrome and highlight the potential for recovery following a protracted course of severe coronavirus disease 2019.

Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity.

The prevalence of obesity is rising worldwide and obese patients comprise a specific population in the intensive care unit. Acute respiratory distress syndrome (ARDS) incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the features of ARDS. In this report, we demonstrate that high fat diet induced obesity increases the severity of hyperoxic acute lung injury in mice in part by altering fatty acid synthase (FASN) levels in the lung. Obese mice exposed to hyperoxia had significantly reduced survival and increased lung damage. Transcriptomic analysis of lung homogenates identified Fasn as one of the most significantly altered mitochondrial associated genes in mice receiving 60% compared to 10% fat diet. FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. Depletion of FASN in type II alveolar epithelial cells resulted in altered mitochondrial bioenergetics and more severe lung injury with hyperoxic exposure, even upon the administration of a 60% fat diet. This is the first study to show that a high fat diet leads to altered FASN expression in the lung and that both a high fat diet and reduced FASN expression in alveolar epithelial cells promote lung injury.

Mitochondrial Dysfunction in Aged Macrophages and Lung during Primary Streptococcus pneumoniae Infection is Improved with Pirfenidone.

Pneumococcal infections remain a leading cause of death in older adults, with the most serious cases occurring in persons ≥65 years of age. There is an urgent need to investigate molecular pathways underlying these impairments and devise new therapeutics to modulate innate immunity. The goal of our current study is to understand the impact of chronological aging on mitochondrial function in response to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using chronologically aged murine models, our findings demonstrate that decreased ATP production is associated with dysregulated mitochondrial complex expression, enhanced oxidative stress, diminished antioxidant responses, and decreased numbers of healthy mitochondria in aged adult macrophages and lung in response to S. pneumoniae. Pre-treatment of aged macrophages with pirfenidone, an anti-fibrotic drug with antioxidant and anti-inflammatory properties, improved mitochondrial function and decreased cellular oxidative stress responses. In vivo administration of pirfenidone decreased superoxide formation, increased healthy mitochondria number, improved ATP production, and decreased inflammatory cell recruitment and pulmonary oedema in aged mouse lung during infection. Taken together, our data shed light on the susceptibility of older persons to S. pneumoniae and provide a possible therapeutic to improve mitochondrial responses in this population.

Safety and long-term efficacy of AAV1.SERCA2a using nebulizer delivery in a pig model of pulmonary hypertension.

Nebulization delivery of adeno-associated virus serotype 1 encoding sarcoplasmic reticulum Ca2+-ATPase2a (AAV1.SERCA2a) gene was examined in a Yukatan miniature swine model of chronic pulmonary hypertension (n = 13). Nebulization of AAV1.SERCA2a resulted in homogenous distribution of vectors, lower pulmonary vascular resistance, and a trend towards better long-term survival compared to control animals.

Dynamic changes of phenotypically different circulating tumor cells sub-populations in patients with recurrent/refractory small cell lung cancer treated with pazopanib.

The aim of the study was to investigate the effect of 2nd-line pazopanib on the different CTCs subpopulations in SCLC patients and evaluate the clinical relevance of their changes. Different CTCs subpopulations were evaluated before pazopanib initiation (n = 56 patients), after one-cycle (n = 35) and on disease progression (n = 45) by CellSearch and double immunofluorescence using anti-CKs and anti-Ki67, anti-M30 or anti-Vimentin antibodies. Before treatment, CTCs were detected in 50% of patients by CellSearch whereas 53.4%, 15.5% and 74.1% patients had CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs, respectively. One pazopanib cycle significantly decreased the number of CTCs as detected by CellSearch (p = 0.043) as well as the number of CK+/Ki67+ (p < 0.001), CK+/M30+ (p = 0.015) and CK+/Vim+ (p < 0.001) cells. On disease progression, both the incidence and CTC numbers were significantly increased (CellSearch, p = 0.027; CK+/Ki67+, p < 0.001; CK+/M30+, p = 0.001 and CK+/Vim+, p < 0.001). In multivariate analysis, the detection of CK+/Vim+ CTCs after one treatment cycle (HR: 7.9, 95% CI: 2.9-21.8; p < 0.001) and CTCs number on disease progression, as assessed by CellSearch, (HR: 2.0, 95% CI: 1.0-6.0; p = 0.005) were emerged as independent factors associated with decreased OS. In conclusion, pazopanib can eliminate different CTC subpopulations in patients with relapsed SCLC. The analysis of CTCs could be used as a dynamic biomarker of treatment efficacy.

Decreased NLRP3 inflammasome expression in aged lung may contribute to increased susceptibility to secondary Streptococcus pneumoniae infection.

Post-viral pneumococcal pneumonia is a leading morbidity and mortality in older patients (≥65years of age). The goal of our current study is to understand the impact of chronological aging on innate immune responses to a secondary, post viral infection with Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using aged murine models of infection, our findings demonstrate increased morbidity and mortality in aged mice within 48h post-secondary S. pneumoniae infection. Increased susceptibility of aged mice was associated with decreased TLR1, TLR6, and TLR9 mRNA expression and diminished IL1ß mRNA expression. Examination of NLRP3 inflammasome expression illustrated decreased NLRP3 mRNA expression and decreased IL1ß production in aged lung in response to secondary S. pneumoniae infection.

Rare case of pulmonary involvement in an adult with Kawasaki disease.

Kawasaki disease is an acute, self-limited, febrile vasculitis typically seen in early childhood. Pulmonary involvement is uncommon and is not part of the conventional diagnostic criteria. We add to the literature a unique case of a 22year-old male with Kawasaki disease and pulmonary involvement. It illustrates the importance of recognizing unusual presentations of Kawasaki disease and highlights the possibility of pulmonary abnormalities on physical and imaging examination. Awareness of such presentations can help avoid delayed diagnosis, prevent the development of coronary aneurysms, and allow careful observation for imaging resolution.

Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension: A Large Animal Model.

BACKGROUND: Pulmonary hypertension (PH) is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca(2+)) homeostasis and transition of pulmonary artery smooth muscle cells to a proliferative phenotype. OBJECTIVES: We assessed the feasibility of sustained pulmonary vascular SERCA2a gene expression using aerosolized delivery of adeno-associated virus type 1 (AAV1) in a large animal model of chronic PH and evaluated the efficacy of gene transfer regarding progression of pulmonary vascular and RV remodeling. METHODS: A model of chronic post-capillary PH was created in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was confirmed hemodynamically, and animals were randomized to intratracheal administration of aerosolized AAV1 carrying the human SERCA2a gene (n = 10, AAV1.SERCA2a group) or saline (n = 10). Therapeutic efficacy was evaluated 2 months after gene delivery. RESULTS: Transduction efficacy after intratracheal delivery of AAV1 was confirmed by ß-galactosidase detection in the distal pulmonary vasculature. Treatment with aerosolized AAV1.SERCA2a prevented disease progression as evaluated by mean pulmonary artery pressure, vascular resistance, and limited vascular remodeling quantified by histology. Therapeutic efficacy was supported further by the preservation of RV ejection fraction (p = 0.014) and improvement of the RV end-diastolic pressure-volume relationship in PH pigs treated with aerosolized AAV1.SERCA2a. CONCLUSIONS: Airway-based delivery of AAV vectors to the pulmonary arteries was feasible, efficient, and safe in a clinically relevant chronic PH model. Vascular SERCA2a overexpression resulted in beneficial effects on pulmonary arterial remodeling, with attendant improvements in pulmonary hemodynamics and RV performance, and might offer therapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases.

Perseverant, non-indicated treatment of obese patients for obstructive lung disease.

BACKGROUND: Bronchodilators are a mainstay of treatment for patients with airflow obstruction. We hypothesized that patients with obesity and no objective documentation of airflow obstruction are inappropriately treated with bronchodilators. METHODS: Spirometric results and medical records of all patients with body mass index >30 kg/m2 who were referred for testing between March 2010 and August 2011 were analyzed. RESULTS: 155 patients with mean age of 52.6 ± (SE)1.1 y and BMI of 38.7 ± 0.7 kg/m2 were studied. Spirometry showed normal respiratory mechanics in 62 (40%), irreversible airflow obstruction in 36 (23.2%), flows suggestive of restriction in 35 (22.6%), reversible obstruction, suggestive of asthma in 11 (7.1%), and mixed pattern (obstructive and restrictive) in 6 (3.9%). Prior to testing, 45.2% (28 of 62) of patients with normal spirometry were being treated with medications for obstructive lung diseases and 33.9% (21 of 62) continued them despite absence of airflow obstruction on spirometry. 60% (21 of 35) of patients with a restrictive pattern in their spirometry received treatment for obstruction prior to spirometry and 51.4% (18 of 35) continued bronchodilator therapy after spirometric testing. There was no independent association of non-indicated treatment with spirometric results, age, BMI, co-morbidities or smoking history. All patients with airflow obstruction on testing who were receiving bronchodilators before spirometry continued to receive them after testing. CONCLUSION: A substantial proportion of patients with obesity referred for pulmonary function testing did not have obstructive lung disease, but were treated nonetheless, before and after spirometry demonstrating absence of airway obstruction.

Clinical consequences of altered chemoreflex control.

Control of ventilation dictates various breathing patterns. The respiratory control system consists of a central pattern generator and several feedback mechanisms that act to maintain ventilation at optimal levels. The concept of loop gain has been employed to describe its stability and variability. Synthesizing all interactions under a general model that could account for every behavior has been challenging. Recent insight into the importance of these feedback systems may unveil therapeutic strategies for common ventilatory disturbances. In this review we will address the major mechanisms that have been proposed as mediators of some of the breathing patterns in health and disease that have raised controversies and discussion on ventilatory control over the years.

Risk factors for development of acute kidney injury in critically ill patients: a systematic review and meta-analysis of observational studies.

Background. Acute kidney injury (AKI) is a frequent complication of critically ill patients. The impact of different risk factors associated with this entity in the ICU setting is unknown. Objectives. The purpose of this research was to assess the risk factors associated with the development of AKI in critically ill patients by meta-analyses of observational studies. Data Extraction. Two reviewers independently and in duplicate used a standardized form to collect data from published reports. Authors were contacted for missing data. The Newcastle-Ottawa scale assessed study quality. Data Synthesis. Data from 31 diverse studies that enrolled 504,535 critically ill individuals from a wide variety of ICUs were included. Separate random-effects meta-analyses demonstrated a significantly increased risk of AKI with older age, diabetes, hypertension, higher baseline creatinine, heart failure, sepsis/systemic inflammatory response syndrome, use of nephrotoxic drugs, higher severity of disease scores, use of vasopressors/inotropes, high risk surgery, emergency surgery, use of intra-aortic balloon pump, and longer time in cardiopulmonary bypass pump. Conclusion. The best available evidence suggests an association of AKI with 13 different risk factors in subjects admitted to the ICU. Predictive models for identification of high risk individuals for developing AKI in all types of ICU are required.

Lung ultrasound in critically ill patients: comparison with bedside chest radiography.

PURPOSE: To compare the diagnostic performance of lung ultrasound and bedside chest radiography (CXR) for the detection of various pathologic abnormalities in unselected critically ill patients, using thoracic computed tomography (CT) as a gold standard. METHODS: Forty-two mechanically ventilated patients scheduled for CT were prospectively studied with a modified lung ultrasound protocol. Four pathologic entities were evaluated: consolidation, interstitial syndrome, pneumothorax, and pleural effusion. Each hemithorax was evaluated for the presence or absence of each abnormality. RESULTS: Eighty-four hemithoraces were evaluated by the three imaging techniques. The sensitivity, specificity, and diagnostic accuracy of CXR were 38, 89, and 49% for consolidation, 46, 80, and 58% for interstitial syndrome, 0, 99, and 89% for pneumothorax, and 65, 81, and 69% for pleural effusion, respectively. The corresponding values for lung ultrasound were 100, 78, and 95% for consolidation, 94, 93, and 94% for interstitial syndrome, 75, 93, and 92% for pneumothorax, and 100, 100, and 100% for pleural effusion, respectively. The relatively low sensitivity of lung ultrasound for pneumothorax could be due to small number of cases (n = 8) and/or suboptimal methodology. CONCLUSIONS: In our unselected general ICU population lung ultrasound has a considerably better diagnostic performance than CXR for the diagnosis of common pathologic conditions and may be used as an alternative to thoracic CT.

Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs.

RATIONALE: Wounded alveolus resident cells are identified in human and experimental acute respiratory distress syndrome models. Poloxamer 188 (P188) is an amphiphilic macromolecule shown to have plasma membrane-sealing properties in various cell types. OBJECTIVES: To investigate whether P188 (1) protects alveolus resident cells from necrosis and (2) is associated with reduced ventilator-induced lung injury in live rats, isolated perfused rat lungs, and scratch and stretch-wounded alveolar epithelial cells. METHODS: Seventy-four live rats and 18 isolated perfused rat lungs were ventilated with injurious or protective strategies while infused with P188 or control solution. Alveolar epithelial cell monolayers were subjected to scratch or stretch wounding in the presence or absence of P188. MEASUREMENTS AND MAIN RESULTS: P188 was associated with fewer mortally wounded alveolar cells in live rats and isolated perfused lungs. In vitro, P188 reduced the number of injured and necrotic cells, suggesting that P188 promotes cell repair and renders plasma membranes more resilient to deforming stress. The enhanced cell survival was accompanied by improvement in conventional measures of lung injury (peak airway pressure, wet-to-dry weight ratio) only in the ex vivo-perfused lung preparation and not in the live animal model. CONCLUSIONS: P188 facilitates plasma membrane repair in alveolus resident cells, but has no salutary effects on lung mechanics or vascular barrier properties in live animals. This discordance may have pathophysiological significance for the interdependence of different injury mechanisms and therapeutic implications regarding the benefits of prolonging the life of stress-activated cells.