Sex, gender and the pulmonary physiology of exercise

In this review, we detail how the pulmonary system's response to exercise is impacted by both sex and gender in healthy humans across the lifespan. First, the rationale for why sex and gender differences should be considered is explored, and then anatomical differences are highlighted, namely that females typically have smaller lungs and airways than males. Thereafter, we describe how these anatomical differences can impact functional aspects such as respiratory muscle energetics and activation, mechanical ventilatory constraints, diaphragm fatigue, and pulmonary gas exchange in healthy adults and children. Finally, we detail how gender can impact the pulmonary response to exercise.

Defibrotide Therapy for Sars CoV2 Acute Respiratory Distress Syndrome

Background: SARS-CoV-2 related acute respiratory distress syndrome (ARDS) is associated with endothelial dysfunction and profound dysregulation of the thrombotic/fibrinolytic pathway, with thrombotic complications common in affected patients (pts). Fibrin deposition may be a key feature of the pathobiology, with markedly elevated levels of PAI-1 reported. Defibrotide (DF), a polyanionic naturally-derived polydeoxyribonucelotide with endothelial stabilizing activity, has fibrinolytic, antithrombotic and anti-inflammatory properties, with known activity in reducing PAI-1 levels and inhibiting heparanase. We now report a prospective, open label, safety and tolerability trial of defibrotide for the management of patients with advanced SARS-CoV-2 related ARDS. Patients and Methods: Eligible patients (pts) were ≥18 years in age, with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-Dimer > 2X ULN, and a positive PCR-based assay for SARS-CoV-2. Concomitant use of systemic anticoagulants or fibrinolytics was initially precluded, with the study amended to allow prophylactic doses of systemic heparin in its latter stages. Defibrotide (6.25 mg/kg/dose IV q. 6 hours) was administered for a planned 7-day course, with day 1 defined as the first day of study therapy. Therapy was able to be discontinued prior to day 7 in pts who met the pulmonary response parameter at that earlier timepoint. Patients with a partial response to therapy (> 20% reduction in FiO2) by day 7 were allowed to receive an additional 7 days of therapy (14 days total). Response was defined as complete cessation of supplemental O2 support, or ≥ 2 point reduction in WHO ordinal score for 48 consecutive hours by day 7. Patients were recruited from a single center between October 2020 and March 2021. Results: Twelve pts (median 63 years, range 35-73 years) were treated, with 10 of 12 pts on mechanical ventilation (median FiO2 55%, PEEP 18 mmHg), and six on vasopressor support at the time of study entry. Baseline PaO2/FiO2 ratios ranged from 82 - 200 mmHg. The median D-Dimer was 3.25 mcg/ml (range 1.33-12.3 mcg/ml), and fibrinogen 637 mg/dl (range 250-1208 mg/dl) at study entry. Dexamethasone and remdesivir had been administered prior to DF in all pts, with no other SARS-CoV-2 targeted treatment given during DF therapy. Eleven pts received ≤7 days of therapy, with one pt receiving 14 days. The first 9 pts received DF without other concomitant anticoagulants, with the last 3 pts concurrently receiving prophylactic heparin plus DF. No hemorrhagic or bleeding complications occurred during DF therapy, including the 3 pts receiving concurrent heparin prophylaxis. Likewise, no thrombotic complications developed during study therapy, including the 9 patients in which DF was their sole anti-coagulant. All 12 patients were evaluable for response. Four pts met the day 7 pulmonary response parameter, with 2 pts having a complete cessation of O2 support within this period. Three pts died from progressive pulmonary disease, at 11, 17 and 34 days from study entry. The 3 pts (who died) had the lowest baseline PaO2/FiO2 ratios (82-115 mmHg) of all study subjects. Nine pts (75%) remain alive, 64 to 174 days from study entry, all 9 discharged from their primary hospitalization. Day 30 all-cause mortality was 17% (95%CI: 0-35%). Serial coagulation and fibrinolytic assays were available in 7 patients. Total PAI-1 levels decreased from a median 167 ng/ml (range 105-264 ng/ml) to a median 104 ng/ml (range 55-166 ng/ml) by day 4 of therapy, with all 7 subjects showing a decline in PAI-1 levels at that time point. Total tPA levels increased from a median 3.02 ng/ml (range 0.72 - 36.1 ng/ml) at baseline to 4.5 ng/ml (range 1.1-8.2 ng/ml) by day 4 in study subjects. Allowing for the small sample size, baseline PAI-1, tPA or D-Dimer levels did not impact response. One of two patients with a baseline D-Dimer > 10 mcg/ml responded, while both patients with a baseline D-Dimer <2.0 mcg/ml failed to meet the response parameter. Conclusion: The use of DF for the management of SARS-CoV-2-related ARDS proved safe and tolerable in a prospective, open label trial. No hemorrhagic or thrombotic complications were reported during therapy. Outcomes were promising, including an overall survival of 75% in a patient population with a historically high mortality rate. (The study was supported by a research grant from Jazz Pharmaceuticals) Disclosures Yanik: Jazz Pharmaceutical: Research Funding. Pipe: Sangamo Therapeutics: Other: Scientific Advisory Board; ASC Therapeutics: Other: Scientific Advisory Board; Apcintex: Consultancy; Bayer: Consultancy; Biomarin: Consultancy; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; Freeline: Consultancy; Grifols: Consultancy; HEMA Biologics: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy. Sisson: Translatebio: Other: Data Safety Committee member. Richardson: Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Secura Bio: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Lawrence: MDI Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Defibrotide: Off label use for ARDS

Comparison of Londrina activities of daily living protocol and Glittre ADL test on cardio-pulmonary response in patients with COPD: a cross-sectional study

Background: In COPD patients it is very important to assess the activities of daily living (ADL) due to an impairment of independence and quality of life. There is a lack of retrievable data regarding the cardio-pulmonary response to Londrina ADL protocol in patients with COPD. The aim of the present study was to assess the cardio-pulmonary response to Londrina ADL protocol in patients with COPD and to compare this with responses to the Glittre ADL test. Methods: This cross-sectional study was done on 30 COPD subjects. Each subject was made to perform the Londrina ADL protocol, Glittre ADL test, twice each, on subsequent days. The Londrina ADL protocol comprises 5 activities representing ADL, involving upper limbs, lower limbs, and trunk movements. The Glittre ADL test consists of completing a circuit while carrying a weighted backpack (2.5 kg for women, 5.0 kg for men). The better value of the two was taken into consideration. For the Londrina ADL protocol and Glittre ADL test the outcome of primary interest was time and for the six-minute walk test was the distance walked. The secondary outcomes for all the tests were heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate, saturation of oxygen in blood and dyspnea.Results: The COPD subjects of age group 63.27±11.07 years took 5.94±0.36 min to complete trial 2 of the Londrina ADL protocol. A significant physiological increase in heart rate (p≤0.01), respiratory rate (p≤0.01), blood pressure (p≤0.01) and severity of dyspnea (p≤0.01) were observed whereas saturation of oxygen in blood (p≤0.01) was reduced at the end of the Londrina ADL protocol and Glittre ADL test. There was a positive, non-significant correlation between the six-minute walk test distance and the Londrina ADL protocol time (r=0.236) (p=0.209). A positive, not significant correlation was observed between the Glittre ADL test (time) and the Londrina ADL protocol (time) (r=0.194) (p=0.304) and a negative but not significant correlation between the six-minute walk test (distance) and the Glittre ADL test (time) (r= -0.184) (p=0.330).Conclusion: The Londrina ADL protocol can be used as an assessment tool to the evaluation of functional performance and activities of daily living in COPD along with other test protocols in pulmonary rehabilitation.

Exposure to nicotine-free and flavor-free e-cigarette vapors modifies the pulmonary response to tobacco cigarette smoke in female mice

Most of electronic cigarette (e-cigarette) users are also smoking tobacco cigarettes. Because of the relative novelty of this habit, very little is known on the impact of vaping on pulmonary health, even less on the potential interactions of dual e-cigarette and tobacco cigarette use. Therefore, we used well-established mouse models to investigate the impact of dual exposure to e-cigarette vapors and tobacco cigarette smoke on lung homeostasis. Groups of female BALB/c mice were exposed to room air, tobacco smoke only, nicotine-free flavor-free e-cigarette vapors only or both tobacco smoke and e-cigarette vapors. Moreover, since tobacco smoke and electronic cigarette vapors both affect circadian processes in the lungs, groups of mice were euthanized at two different time points during the day. We found that dual-exposed mice had altered lung circadian gene expression compared with mice exposed to tobacco smoke alone. Dual-exposed mice also had different frequencies of dendritic cells, macrophages, and neutrophils in the lung tissue compared with mice exposed to tobacco smoke alone, an observation also valid for B-lymphocytes and CD4+ and CD8+ T lymphocytes. Exposure to e-cigarette vapors also impacted the levels of immunoglobulins in the bronchoalveolar lavage and serum. Finally, e-cigarette and dual exposures increased airway resistance compared with mice exposed to room air or tobacco smoke alone, respectively. Taken together, these data suggest that e-cigarette vapors, even without nicotine or flavors, could affect how the lungs react to tobacco cigarette smoke exposure in dual users, potentially altering the pathological course triggered by smoking.

Morphological and Mechanistic Aspects of Thiourea-Induced Acute Lung Injury and Tolerance in the Rat

Thiourea-based molecules cause pulmonary edema when administered to rats at relatively low doses. However, rats survive normally lethal doses after prior exposure to a lower, nonlethal dose; this phenomenon is known as tolerance. The present study investigated the morphological and functional aspects of acute lung injury (ALI) induced by methylphenylthiourea (MPTU) in the Wistar rat and the pulmonary response involved in prevention of the injury. We identified pulmonary endothelial cells as the main target of acute MPTU injury; they exhibited ultrastructural alterations that can result in increased vascular permeability. In tolerant rats, the lungs showed only transient endothelial changes, at 24-hour post dosing, and mild type II pneumocyte hyperplasia on day 7 post dosing. They exhibited glutathione levels similar to the controls and increased expression of flavin-containing monooxygenase 1 (FMO1), the enzyme responsible for bioactivation of small thioureas in the laboratory rat. Incubation of rat pulmonary microsomal preparations with MPTU inhibited FMO activity, indicating that tolerance is related to irreversible inhibition of FMOs. The rat model of thiourea-induced pulmonary toxicity and tolerance represents an interesting approach to investigate certain aspects of the pathogenesis of ALI and therapeutic approaches to lung diseases, such as acute respiratory distress syndrome.