Epinephrine evokes shortening of human airway smooth muscle cells following ß2 adrenergic receptor desensitization.

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α1-adrenergic receptors (α1ARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on α1ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating ß2-adrenergic receptors (ß2ARs). Conventionally, the selective ß2AR agonism of EPI was thought to be, in part, due to a predominance of ß2ARs and/or a sparse, or lack of α1AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α1AR subtype B) and identify a spontaneous "switch-like" activation of α1ARs that evokes intracellular calcium, myosin light chain phosphorylation, and HASM cell shortening. The switch-like responses, and related EPI-induced biochemical and mechanical signals, emerged upon pharmacological inhibition of ß2ARs and/or under experimental conditions that induce ß2AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an α1AR antagonist, doxazosin mesylate (DM). These data collectively uncover a previously unrecognized feed-forward mechanism driving bronchospasm via two distinct classes of G protein-coupled receptors (GPCRs) and provide a basis for reexamining α1AR inhibition for the management of stress/exercise-induced asthma and/or ß2-agonist insensitivity in patients with difficult-to-control, disease subtypes.

MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study.

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure. Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results: tPA was associated with significant PaO2/FiO2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO2/FiO2 ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration. Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population.

A Simple Scoring Tool to Predict Medical Intensive Care Unit Readmissions Based on Both Patient and Process Factors.

BACKGROUND: Although many predictive models have been developed to risk assess medical intensive care unit (MICU) readmissions, they tend to be cumbersome with complex calculations that are not efficient for a clinician planning a MICU discharge. OBJECTIVE: To develop a simple scoring tool that comprehensively takes into account not only patient factors but also system and process factors in a single model to predict MICU readmissions. DESIGN: Retrospective chart review. PARTICIPANTS: We included all patients admitted to the MICU of Robert Wood Johnson University Hospital, a tertiary care center, between June 2016 and May 2017 except those who were < 18 years of age, pregnant, or planned for hospice care at discharge. MAIN MEASURES: Logistic regression models and a scoring tool for MICU readmissions were developed on a training set of 409 patients, and validated in an independent set of 474 patients. KEY RESULTS: Readmission rate in the training and validation sets were 8.8% and 9.1% respectively. The scoring tool derived from the training dataset included the following variables: MICU admission diagnosis of sepsis, intubation during MICU stay, duration of mechanical ventilation, tracheostomy during MICU stay, non-emergency department admission source to MICU, weekend MICU discharge, and length of stay in the MICU. The area under the curve of the scoring tool on the validation dataset was 0.76 (95% CI, 0.68-0.84), and the model fit the data well (Hosmer-Lemeshow p = 0.644). Readmission rate was 3.95% among cases in the lowest scoring range and 50% in the highest scoring range. CONCLUSION: We developed a simple seven-variable scoring tool that can be used by clinicians at MICU discharge to efficiently assess a patient's risk of MICU readmission. Additionally, this is one of the first studies to show an association between MICU admission diagnosis of sepsis and MICU readmissions.

Observational study of the use of recombinant tissue-type plasminogen activator in COVID-19 shows a decrease in physiological dead space.

#COVID19-induced ARDS is partly explained by the presence of microthrombi, motivating the use of thrombolytics. This study shows that thrombolytics decrease dead space ventilation in COVID-19 ARDS patients. https://bit.ly/2GdM44a.

Budesonide enhances agonist-induced bronchodilation in human small airways by increasing cAMP production in airway smooth muscle.

The nongenomic mechanisms by which glucocorticoids modulate ß2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision-cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX), or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone, and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX, or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation and that potentially mediated the rapid effects of steroids on ß2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor-α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and ß2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease.

Obesity increases airway smooth muscle responses to contractile agonists.

The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an intrinsic difference between human airway smooth muscle (HASM) cells derived from nonobese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC), and greater shortening in HASM cells derived from obese subjects. HASM cells derived from nonobese and obese subjects were age and sex matched. Phosphorylation of MLC was measured after having been stimulated by carbachol. Carbachol- or histamine-induced mobilization of calcium and cell shortening were assessed in HASM cells derived from nonobese and obese donors. Agonist-induced MLC phosphorylation, mobilization of calcium, and cell shortening were greater in obese compared with non-obese-derived HASM cells. The MLC response was comparable in HASM cells derived from obese nonasthma and nonobese fatal asthma subjects. HASM cells derived from obese female subjects were more responsive to carbachol than HASM cells derived from obese male subjects. Insulin pretreatment had little effect on these responses. Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.

Impact of gram negative bacteria airway recolonization on the occurrence of chronic lung allograft dysfunction after lung transplantation in a population of cystic fibrosis patients.

BACKGROUND: Chronic Lung Allograft Dysfunction (CLAD) is the main cause of morbidity and mortality after the first year following lung transplantation (LTx). Risk factors of CLAD have been extensively studied, but the association between gram-negative bacteria (GNB) bronchial colonization and the development of CLAD is controversial. The purpose of our study was to investigate the association between post-transplant recolonization with the same species or de-novo colonization with a new GNB species and CLAD. The same analysis was performed on a sub-group of patients at the strain level using Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry technique. RESULTS: Forty adult cystic fibrosis (CF) patients who underwent a first bilateral LTx in the University Hospital of Marseille, between January 2010 and December 2014, were included in the study. Patients with GNB de-novo colonization had a higher risk of developing CLAD (OR = 6.72, p = 0.04) and a lower rate of CLAD-free survival (p = 0.005) compared to patients with GNB recolonization. No conclusion could be drawn from the subgroup MALDI-TOF MS analysis at the strain level. CONCLUSION: Post-LTx GNB airway recolonization seems to be a protective factor against CLAD, whereas de-novo colonization with a new species of GNB seems to be a risk factor for CLAD.

Switch of noninvasive ventilation (NIV) to continuous positive airway pressure (CPAP) in patients with obesity hypoventilation syndrome: a pilot study.

BACKGROUND: Obesity is a major worldwide public health issue. The main respiratory complication stemming from obesity is obesity hypoventilation syndrome (OHS). Most of the OHS patients diagnosed during an exacerbation are treated with non invasive ventilation (NIV). Up to date, no prospective study has demonstrated in real life conditions the feasibility of a systematic protocoled switch of NIV to continuous positive airway pressure (CPAP), once stability is achieved. METHODS: In this prospective study, we included stable patients with OHS, with moderate to severe concomitant obstructive sleep apnea (OSA) and without obstructive pulmonary disease, who had been undergoing NIV for more than 2 months. The following measurements were performed, first with NIV and then after the switch to CPAP: diurnal arterial blood gas measurements; nocturnal oximetry and capnometry; mean compliance and AHI; measures of quality of life and quality of sleep. RESULTS: 22/30 patients accepted to participate in the study and 15/22 patients completed the study. There were no significant differences for pooled data in diurnal alveolar blood gases, nocturnal capnometry (p = 0.534), nocturnal oximetry (p = 0.218), mean compliance (p = 0.766), mean AHI (p = 0.334), quality of life or quality of sleep. Eighty percent of the patients treated in this study favored CPAP over NIV. CONCLUSION: This pilot study showed in real life conditions the possibility of a systematic switch of NIV to CPAP, in most stable patients with OHS, with similar efficacy on diurnal and nocturnal alveolar gas exchange, quality of life and quality of sleep. TRIAL REGISTRATION: ISRCTN13981084 . Registered: 27 February 2017 (retrospectively registered).