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Background: Minimally invasive thoracic surgery is associated with substantial pain that can impair pulmonary function. Fascial plane blocks may offer a favorable alternative to opioids, but conventional local anesthetics provide a limited duration of analgesia. We therefore tested the primary hypothesis that a mixture of liposomal bupivacaine and plain bupivacaine improves the overall benefit of analgesia score (OBAS) during the first three postoperative days compared to bupivacaine alone. Secondarily, we tested the hypotheses that liposomal bupivacaine improves respiratory mechanics, and decreases opioid consumption., Methods: Adults scheduled for robotically or video-assisted thoracic surgery with combined ultrasound-guided pectoralis II and serratus anterior plane block were randomized to bupivacaine or bupivacaine combined with liposomal bupivacaine. OBAS was measured on postoperative days 1-3 and was analyzed with a linear mixed regression model. Postoperative respiratory mechanics were estimated using a linear mixed model. Total opioid consumption was estimated with a simple linear regression model., Results: We analyzed 189 patients, of whom 95 were randomized to the treatment group and 94 to the control group. There was no significant treatment effect on total OBAS during the initial three postoperative days, with an estimated geometric mean ratio of 0.93 (95% CI: 0.76, 1.14; p = 0.485). There was no observed treatment effect on respiratory mechanics, total opioid consumption, or pain scores. Average pain scores were low in both groups., Conclusions: Liposomal bupivacaine did not improve OBAS during the initial postoperative three days following minimally invasive thoracic procedures. Furthermore, there was no improvement in respiratory mechanics, no reduction in opioid consumption, and no decrease in pain scores. Thus, the data presented here does not support the use of liposomal bupivacaine over standard bupivacaine to enhance analgesia after minimally invasive thoracic surgery., Summary Statement: For minimally invasive thoracic procedures, addition of liposomal bupivacaine to plain bupivacaine for thoracic fascial plane blocks does not improve OBAS, reduce opioid requirements, improve postoperative respiratory mechanics, or decrease pain scores., Competing Interests: Declaration of competing interest Sudish Murthy is a consultant for Advanced Medical Solutions, LLC, an advisor for Lazzaro Medical, and received honoraria from Intuitive Surgical and Medtronic; Alparslan Turan is a consultant for Civco medical and received a research grant from Pacira Pharmaceuticals. Daniel I Sessler - is a consultant for Pacira Pharmaceuticals. Other authors have no conflicts of interest to declare. Sudish Murthy is a consultant for Advanced Medical Solutions, LLC, an advisor for Lazzaro Medical, and received honoraria from Intuitive Surgical and Medtronic; Alparslan Turan is a consultant for Civco medical and received a research grant from Pacira Pharmaceuticals. All other authors declare no conflicts of interest. Pacira Pharmaceuticals was not involved in the data collection, data analysis, preparation of paper, or the decision to submit. The manuscript was not shared with the sponsor., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Brain death (BD) compromises the viability of the lung for donation. Hypertonic saline solution (HSS) induces rapid intravascular volume expansion and immunomodulatory action. We investigated its role in ventilatory mechanics (VMs) and in the inflammatory activity of the lungs of rats subjected to BD., Methods: Wistar rats were divided into four groups: control, n = 10: intact rats subjected to extraction of the heart-lung block; BD, n = 8 (BD): rats treated with isotonic saline solution (4 mL/kg) immediately after BD; hypertonic saline 0 h, n = 9 (Hip.0'): rats treated with HSS (4 mL/kg) immediately after BD; and hypertonic saline 1 h, n = 9 (Hip.60'), rats treated with HSS (4 mL/kg) 60 min after BD. The hemodynamic characteristics, gas exchange, VMs, inflammatory mediators, and histopathological evaluation of the lung were evaluated over 240 min of BD., Results: In VMs, we observed increased airway resistance, tissue resistance, tissue elastance, and respiratory system compliance in the BD group (P < 0.037), while the treated groups showed no impairment over time (P > 0.05). In the histological analysis, the BD group showed a greater area of perivascular edema and a higher neutrophil count than the control group and the Hip.60' group (P < 0.05)., Conclusions: Treatment with HSS was effective in preventing changes in the elastic and resistive pulmonary components, keeping them at baseline levels. Late treatment reduced perivascular and neutrophilic edema in lung tissue., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of bronchodilator on the respiratory mechanics and pulmonary function of children and adolescents with cystic fibrosis., Methods: Cross-sectional study on clinically stable children and adolescents with cystic fibrosis aged from six to 15 years. Participants underwent impulse oscillometry and spirometry evaluations before and 15 minutes after bronchodilator inhalation. The Kolmogorov-Smirnov test was applied to verify the sample distribution, and the Student's t-test and Wilcoxon test were used to compare the data before and after bronchodilator inhalation., Results: The study included 54 individuals with a mean age of 9.7±2.8 years. The analysis showed a statistically significant improvement in impulse oscillometry and spirometry parameters after bronchodilator inhalation. However, according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommendations (2020 and 2021), this improvement was not sufficient to classify it as a bronchodilator response., Conclusions: The use of bronchodilator medication improved respiratory mechanics and pulmonary function parameters of children and adolescents with cystic fibrosis; however, most patients did not show bronchodilator response according to ATS/ERS recommendations.

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED 50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED 50  = 0.96 mg/kg) > 3-furanylfentanyl (ED 50  = 2.60 mg/kg) > crotonylfentanyl (ED 50  = 2.72 mg/kg) > para-methoxyfentanyl (ED 50  = 3.31 mg/kg) > buprenorphine (ED 50  = 10.8 mg/kg) > isobutyrylfentanyl (ED 50  = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED 50  = 16.1 mg/kg) > thiophenefentanyl (ED 50  = 18.0 mg/kg) > morphine (ED 50  = 55.3 mg/kg) > benzodioxolefentanyl (ED 50  = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: In mechanically ventilated patients, deep sedation is often assumed to induce "respirolysis," that is, lyse spontaneous respiratory effort, whereas light sedation is often assumed to preserve spontaneous effort. This study was conducted to determine validity of these common assumptions, evaluating the association of respiratory drive with sedation depth and ventilator-free days in acute respiratory failure., Design: Prospective cohort study., Setting: Patients were enrolled during 2 month-long periods in 2016-2017 from five ICUs representing medical, surgical, and cardiac specialties at a U.S. academic hospital., Patients: Eligible patients were critically ill adults receiving invasive ventilation initiated no more than 36 hours before enrollment. Patients with neuromuscular disease compromising respiratory function or expiratory flow limitation were excluded., Interventions: Respiratory drive was measured via P0.1, the change in airway pressure during a 0.1-second airway occlusion at initiation of patient inspiratory effort, every 12 ± 3 hours for 3 days. Sedation depth was evaluated via the Richmond Agitation-Sedation Scale. Analyses evaluated the association of P0.1 with Richmond Agitation-Sedation Scale (primary outcome) and ventilator-free days., Measurements and Main Results: Fifty-six patients undergoing 197 bedside evaluations across five ICUs were included. P0.1 ranged between 0 and 13.3 cm H2O (median [interquartile range], 0.1 cm H2O [0.0-1.3 cm H2O]). P0.1 was not significantly correlated with the Richmond Agitation-Sedation Scale (RSpearman, 0.02; 95% CI, -0.12 to 0.16; p = 0.80). Considering P0.1 terciles (range less than 0.2, 0.2-1.0, and greater than 1.0 cm H2O), patients in the middle tercile had significantly more ventilator-free days than the lowest tercile (incidence rate ratio, 0.78; 95% CI, 0.65-0.93; p < 0.01) or highest tercile (incidence rate ratio, 0.58; 95% CI, 0.48-0.70; p < 0.01)., Conclusions: Sedation depth is not a reliable marker of respiratory drive during critical illness. Respiratory drive can be low, moderate, or high across the range of routinely targeted sedation depth., Competing Interests: Dr. Beitler’s institution received funding from the National Institutes of Health (NIH); he received funding from Hamilton Medical and Sedana Medical; he received support for article research from the NIH. Drs. Dzierba, Khalil, Derry, and Madahar have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Acute intermittent hypoxia (AIH) modifies the functioning of the respiratory network, causing respiratory motor facilitation in anesthetized animals and a compensatory increase in pulmonary ventilation in freely behaving animals. However, it is still unclear whether the ventilatory facilitation induced by AIH in unanesthetized animals is associated with changes in the respiratory pattern. We found that Holtzman male rats (80-150 g) exposed to AIH (10 × 6% O 2 for 30-40 s every 5 min, n = 9) exhibited a prolonged (30 min) increase in baseline minute ventilation (P < 0.05) compared to control animals (n = 13), combined with the occurrence of late expiratory peak flow events, suggesting the presence of active expiration. The increase in ventilation after AIH was also accompanied by reductions in arterial CO 2 and body temperature (n = 5-6, P < 0.05). The systemic treatment with ketanserin (a 5-HT 2 receptor antagonist) before AIH prevented the changes in ventilation and active expiration (n = 11) but potentiated the hypothermic response (n = 5, P < 0.05) when compared to appropriate control rats (n = 13). Our findings indicate that the ventilatory long-term facilitation elicited by AIH exposure in unanesthetized rats is linked to the generation of active expiration by mechanisms that may depend on the activation of serotonin receptors. In contrast, the decrease in body temperature induced by AIH may not require 5-HT 2 receptor activation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Thyroid hormones (THs) are essential for foetal brain development. Because the gestating mother is the main source of THs to the foetus, maternal hypothyroidism and/or premature birth compromise neurological outcomes in the offspring. Respiratory instability and recurrent apneas due to immaturity of the respiratory control network are major causes of morbidity in infants. Inadequate TH supply may be sufficient to delay perinatal maturation of the respiratory control system; however, this hypothesis remains untested. To address this issue, maternal hypothyroidism was induced by adding methimazole (MMI; 0.02% w/v) to the drinking water of pregnant dams from conception to postpartum day 4 (P4). The effect of TH supplementation on respiratory function was tested by injecting levothyroxine (L-T4) in newborns at P1. Respiratory function was assessed by plethysmography (in vivo) and recording of phrenic output from medullary preparations (in vitro). By comparison with controls, TH deficiency increased the frequency of apneas and decreased basal ventilation in vivo and prevented the age-dependent increase in phrenic burst frequency normally observed in vitro. The effects of TH deficiency on GABAergic modulation of respiratory activity were measured by bath application of muscimol (GABA A agonist) or bicuculline (GABA A antagonist). The phrenic burst frequency responses to GABAergic agents were consistently greater in preparations from TH deficient pups. L-T4 supplementation reversed part of the respiratory anomalies related to MMI treatment in vitro. We conclude that TH deficiency during the perinatal period is sufficient to delay maturation of the respiratory control network development. Excessive GABAergic inhibition may contribute to this effect., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in this study. The harmonic distortion index (k d ) was used to assess the respiratory system nonlinearity. The analysis of variance showed difference between groups (OVA vs control) and among doses for both protocols. Bolus protocol posttest: there was a difference between OVA and control at 0.3 and 1 mg/kg doses (p<0.0001 and p<0.001) for R n . Infusion: there was a difference between OVA and control at 192 μg.kg -1 .min -1 dose for R n , G and H, (p<0.01; p<0.001; p<0.001). An increment was found in k d values near to the observed peak values in bolus protocol. The bolus protocol could better differentiate inflamed and non-inflamed airway resistance, whereas the differences between OVA and control in continuous infusion protocol were associated to airway- and, mainly, parenchyma-related parameters. Moreover, the bolus protocol presented a higher nonlinear degree compared to the infusion protocol., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Orexin neurons are active in wakefulness and mostly silent in sleep. In adult rats and humans, orexin facilitates the hypercapnic ventilatory response but has little effect on resting ventilation. The influence of orexin on breathing in the early postnatal period, and across states of vigilance, have not been investigated. This is relevant as the orexin system may be impaired in Sudden Infant Death Syndrome (SIDS) cases. We addressed three hypotheses: 1 ) orexin provides a drive to breathe in infancy; 2 ) the effect of orexin depends on stage of postnatal development; and 3 ) orexin has a greater influence on breathing in wakefulness compared with sleep. Whole body plethysmography was used to monitor breathing of infant rats at three ages: postnatal days ( P ) 7-8 , 12-14 , and 17-19 . Respiratory variables were analyzed in wakefulness (W), quiet sleep (QS), and active sleep (AS), following suvorexant (5 mg/kg ip), a dual orexin receptor antagonist, or vehicle (DMSO). Effects of suvorexant on ventilatory responses to graded hypercapnia ([Formula: see text] = 0.02, 0.04, 0.06), hypoxia ([Formula: see text] = 0.10), and hyperoxia ([Formula: see text] = 1.0) at P12-14 were also tested. At P12-14 , but not at other ages, suvorexant significantly reduced respiratory frequency in all states, reduced the ventilatory equivalent in QW and QS, and increased [Formula: see text] to ∼5 mmHg. Suvorexant had no effect on ventilatory responses to graded hypercapnia or hypoxia. Hyperoxia eliminated the effects of suvorexant on respiratory frequency at P12-14 . Our data suggest that orexin preserves eupneic frequency and ventilation in rats, specifically at ∼2 wk of age, perhaps by facilitating tonic peripheral chemoreflex activity.

Exposure to phosphine (PH 3 ) presents with a host of diverse, non-specific symptoms that span multiple organ systems and is characterized by a high mortality rate. While a comprehensive mechanism for PH 3 poisoning remains inconclusive, prior studies have implicated cardiac failure and circulatory compromise as potential pathways central to PH 3 -induced mortality. In this study, milrinone (MLR), a phosphodiesterase-3 inhibitor used to treat cardiac failure, was investigated as a potential countermeasure for PH 3 poisoning. Lethality, physiological responses, and behavioral changes were evaluated in telemetrized female rats pretreated with water (sham) or one of three doses of MLR (40, 200, or 600 μg/kg) and exposed to PH 3 (660 ppm for 25-40 min; 16,500-26,400 ppm × min). Animals receiving prophylactic administration of 600 μg/kg of MLR had nominally improved survivability compared to sham animals, although median lethal concentration-time and time of death did not differ substantially between treatment groups. Changes in respiration and behavior induced by PH 3 appeared largely unaffected by MLR pretreatment, regardless of dose. Conversely, MLR pretreatment alleviated some aspects of PH 3 -induced cardiac function impairment, with slight dose-dependent effects observed for cardiac contractility, mean arterial pressure, and QRS duration. Together, these results illustrate the importance of circulatory compromise in PH 3 poisoning and highlight the potential viability of MLR as a potential countermeasure option or part of a countermeasure regimen when administered prophylactically at 600 μg/kg., (Copyright © 2018. Published by Elsevier Inc.)

The role of noninvasive positive pressure ventilation (NIPPV) in COVID-19 patients with acute hypoxemic respiratory failure (AHRF) is uncertain, as no direct evidence exists to support NIPPV use in such patients. We retrospectively assessed the effectiveness and safety of NIPPV in a cohort of COVID-19 patients consecutively admitted to the COVID-19 general wards of a medium-size Italian hospital, from March 6 to May 7, 2020. Healthcare workers (HCWs) caring for COVID-19 patients were monitored, undergoing nasopharyngeal swab for SARS-CoV-2 in case of onset of COVID-19 symptoms, and periodic SARS-CoV-2 screening serology. Overall, 50 patients (mean age 74.6 years) received NIPPV, of which 22 (44%) were successfully weaned, avoiding endotracheal intubation (ETI) and AHRF-related death. Due to limited life expectancy, 25 (50%) of 50 NIPPV-treated patients received a "do not intubate" (DNI) order. Among these, only 6 (24%) were weaned from NIPPV. Of the remaining 25 NIPPV-treated patients without treatment limitations, 16 (64%) were successfully weaned, 9 (36%) underwent delayed ETI and, of these, 3 (33.3%) died. NIPPV success was predicted by the use of corticosteroids (OR 15.4, CI 1.79-132.57, p 0.013) and the increase in the PaO 2 /FiO 2 ratio measured 24-48 h after NIPPV initiation (OR 1.02, CI 1-1.03, p 0.015), while it was inversely correlated with the presence of a DNI order (OR 0.03, CI 0.001-0.57, p 0.020). During the study period, 2 of 124 (1.6%) HCWs caring for COVID-19 patients were diagnosed with SARS-CoV-2 infection. Apart from patients with limited life expectancy, NIPPV was effective in a substantially high percentage of patients with COVID-19-associated AHRF. The risk of SARS-CoV-2 infection among HCWs was low., (© 2020. Società Italiana di Medicina Interna (SIMI).)

Propofol is the most commonly used intravenous anesthetic worldwide. It can induce loss of consciousness prior to the occurrence of severe respiratory suppression, which is also a pharmacodynamic feature of all general anesthetics. However, the neural mechanisms underlying this natural phenomenon are controversial and highly related to patient safety. In the present study, we demonstrated that the pharmacodynamic effects of propofol (50 and 100 μM) on suppression of consciousness-related excitatory postsynaptic currents in the medial prefrontal cortex (mPFC) and centromedian nucleus of the thalamus (CMT) were lower than those in the kernel respiratory rhythmogenesis nucleus pre-Bötzinger complex (PrBo). Furthermore, we unexpectedly found that the GABAA receptor β3 subunit is the key target for propofol's action and that it is mutually and exclusively expressed in GABAergic neurons. It is also more abundant in the mPFC and CMT, but mainly co-localized with GABAergic neurons in the PrBo. As a result, the differentiated expression pattern should mediate more neuron suppression through the activation of GABAergic neurons in the mPFC and CMT at low doses of propofol (50 μM). However, PrBo GABAergic neurons were only activated by propofol at a high dose (100 μM). These results highlight the detailed pharmacodynamic effects of propofol on consciousness-related and respiration-related nuclei and provide the distinct interaction mechanism between the β3 subunit and GABAergic neurons in mediating the suppression of consciousness compared to the inhibition of respiration., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

What Is Known and Objective: Propofol provides a prominent sedation effect in gastroscopy. However, sedation with propofol alone during gastroscopy might result in circulatory and respiratory depression. This study aimed to test the hypothesis that the addition of intravenous lidocaine to propofol-based sedation could decrease the ED50 of propofol induction dose during gastroscopy in adult patients while the respiratory and haemodynamic stability were not compromised., Methods: Patients undergoing gastroscopy were randomly enrolled into lidocaine + propofol (L + P) group or normal saline + propofol (NS + P) group. Subjects were initially administered intravenous bolus of 1.5 mg/kg lidocaine in L + P group or equivalent volume of 0.9% saline in NS + P group. Anaesthesia was then induced with a single bolus of 1.0 μg sufentanil followed by injection of propofol in all patients. The induction dose of propofol for each individual patient was determined by the protocol of Dixon "up-and-down" method for both groups. The primary end point was the ED50 of propofol induction dose., Results: Totally, 48 patients were enrolled and completed this study. Compared with the NS + P group, the ED50 of propofol induction dose was significantly reduced in the L + P group (2.01 mg/kg vs. 1.69 mg/kg) (U = 61.5, p < 0.001)., What Is New and Conclusion: The addition of intravenous lidocaine significantly reduced the ED50 of propofol induction dose during gastroscopy in adult patients., Trial Registration: The present clinical trial was registered at http://www.chictr.org.cn/ (registration No. ChiCTR1900024025, 23 June 2019)., (© 2020 John Wiley & Sons Ltd.)

Assessment of respiratory mechanics extends from basic research and animal modeling to clinical applications in humans. However, to employ the applications in human models, it is desirable and sometimes mandatory to study non-human animals first. To acquire further precise and controlled signals and parameters, the animals studied must be further distant from their spontaneous ventilation. The majority of respiratory mechanics studies use positive pressure ventilation to model the respiratory system. In this scenario, a few drug categories become relevant: anesthetics, muscle blockers, bronchoconstrictors, and bronchodilators. Hence, the main objective of this study is to briefly review and discuss each drug category, and the impact of a drug on the assessment of respiratory mechanics. Before and during the positive pressure ventilation, the experimental animal must be appropriately sedated and anesthetized. The sedation will lower the pain and distress of the studied animal and the plane of anesthesia will prevent the pain. With those drugs, a more controlled procedure is carried out; further, because many anesthetics depress the respiratory system activity, a minimum interference of the animal's respiration efforts are achieved. The latter phenomenon is related to muscle blockers, which aim to minimize respiratory artifacts that may interfere with forced oscillation techniques. Generally, the respiratory mechanics are studied under appropriate anesthesia and muscle blockage. The application of bronchoconstrictors is prevalent in respiratory mechanics studies. To verify the differences among studied groups, it is often necessary to challenge the respiratory system, for example, by pharmacologically inducing bronchoconstriction. However, the selected bronchoconstrictor, doses, and administration can affect the evaluation of respiratory mechanics. Although not prevalent, studies have applied bronchodilators to return (airway resistance) to the basal state after bronchoconstriction. The drug categories can influence the mathematical modeling of the respiratory system, systemic conditions, and respiratory mechanics outcomes.

Eupnea and gasping in infancy depend on central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT). Although previous in vitro preparations have provided some evidence that 5-HT acts through type 2 A receptors (5-HT 2A ) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT 2A receptor activation is necessary for eupnea and the proper generation of gasping in vivo. To test this, we administered 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25 mg/kg i.p.), a 5-HT 2A agonist, 8-hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT 1A agonist, or vehicle (saline) to 7-9-day-old tryptophan hydroxylase 2 knockout (TPH2 -/- ) mice. A second experiment assessed the effect of MDL-11,939 (MDL; 10 mg/kg i.p.), the specific 5-HT 2A antagonist, or vehicle (DMSO) on the gasping of wild-type (TPH2 +/+ ) animals. Drugs were given 15 min prior to five episodes of severe hypoxia that elicited gasping. TPH2 -/- breathed more slowly but had the same V̇e and V̇e/V̇o 2 compared with TPH2 +/+ . As previously reported, the gasping of TPH2 -/- was significantly delayed ( P < 0.001) and occurred at a significantly lower frequency compared with TPH2 +/+ ( P = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on V̇e or V̇e/V̇o 2 . The gasping of TPH2 -/- , although unaffected by 8-OH-DPAT, was indistinguishable from the gasping of TPH2 +/+ following DOI. In TPH2 +/+ , application of MDL led to hypoventilation ( P = 0.01), a delay in the appearance of gasping ( P = 0.005), and reduced gasp frequency ( P = 0.05). These data show that, in vivo, 5-HT 2A receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT 2A probably promotes gasping by exciting hypoxia-resistant pacemaker neurons. NEW & NOTEWORTHY Previous in vitro studies suggest that 5-HT 2A receptors contribute to eupnea and are necessary for fictive gasping. The current study shows that the impaired gasping displayed by neonatal TPH2 -/- mice, deficient in CNS serotonin, is restored by 5-HT 2A receptor activation. Following 5-HT 2A blockade, wild-type mice hypoventilated and their gasping resembled that of TPH2 -/- mice. This study shows that both eupnea and gasping in vivo rely on the activation of 5-HT 2A receptors.

We aimed at evaluating the anti-asthmatic effect of cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3 (FOR811A), a nitrosyl-ruthenium compound, in a murine model of allergic asthma. The anti-asthmatic effects were analyzed by measuring the mechanical lung and morphometrical parameters in female Swiss mice allocated in the following groups: untreated control (Ctl+Sal) and control treated with FOR811A (Ctl+FOR), along asthmatic groups untreated (Ast+Sal) and treated with FOR811A (Ast+FOR). The drug-protein interaction was evaluated by in-silico assay using molecular docking. The results showed that the use of FOR811A in experimental asthma (Ast+FOR) decreased the pressure-volume curve, hysteresis, tissue elastance, tissue resistance, and airway resistance, similar to the control groups (Ctl+Sal; Ctl+FOR). However, it differed from the untreated asthmatic group (Ast+Sal, p<0.05), indicating that FOR811A corrected the lung parenchyma and relaxed the smooth muscles of the bronchi. Similar to control groups (Ctl+Sal; Ctl+FOR), FOR811A increased the inspiratory capacity and static compliance in asthmatic animals (Ast+Sal, p<0.05), showing that this metallodrug improved the capacity of inspiration during asthma. The morphometric parameters showed that FOR811A decreased the alveolar collapse and kept the bronchoconstriction during asthma. Beyond that, the molecular docking using FOR811A showed a strong interaction in the distal portion of the heme group of the soluble guanylate cyclase, particularly with cysteine residue (Cys141). In summary, FOR811A relaxed bronchial smooth muscles and improved respiratory mechanics during asthma, providing a protective effect and promising use for the development of an anti-asthmatic drug., Competing Interests: The authors have declared that no competing interests exist.

Delivery of medications to preterm neonates receiving non-invasive ventilation (NIV) represents one of the most challenging scenarios for aerosol medicine. This challenge is highlighted by the undersized anatomy and the complex (patho)physiological characteristics of the lungs in such infants. Key physiological restraints include low lung volumes, low compliance, and irregular respiratory rates, which significantly reduce lung deposition. Such factors are inherent to premature birth and thus can be regarded to as the intrinsic factors that affect lung deposition. However, there are a number of extrinsic factors that also impact lung deposition: such factors include the choice of aerosol generator and its configuration within the ventilation circuit, the drug formulation, the aerosol particle size distribution, the choice of NIV type, and the patient interface between the delivery system and the patient. Together, these extrinsic factors provide an opportunity to optimize the lung deposition of therapeutic aerosols and, ultimately, the efficacy of the therapy.In this review, we first provide a comprehensive characterization of both the intrinsic and extrinsic factors affecting lung deposition in premature infants, followed by a revision of the clinical attempts to deliver therapeutic aerosols to premature neonates during NIV, which are almost exclusively related to the non-invasive delivery of surfactant aerosols. In this review, we provide clues to the interpretation of existing experimental and clinical data on neonatal aerosol delivery and we also describe a frame of measurable variables and available tools, including in vitro and in vivo models, that should be considered when developing a drug for inhalation in this important but under-served patient population.

Background: COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV 1 have been documented previously. However, the precise nature of this deterioration and mechanisms by which evening bronchodilation may mitigate this occurrence have not been studied., Research Question: What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)?, Study Design and Methods: A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 μg) or placebo on morning trough IC (12 h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12 h after the dose and compared with sleeping IND., Results: Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12 h after the dose (P = .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12 h after the dose, and IC for 10 h after the dose were improved (P < .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P < .05) with no change in ventilation or breathing pattern., Interpretation: Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Patient ventilatory dyssynchrony (PVD) is a mismatch between the respiratory drive of the patient and ventilatory assistance. It is a complex event seen in almost all ventilated patients and at any ventilator mode, with uncertain significance and prognosis. Due to its different pathophysiological mechanisms, there is still not consensual classification to guide us in selecting the best treatment. In the present review we aimed to summarize some clinical data on PVD, and to propose a clinical classification based on the type of PVD, from potentially innocuous to clearly harmful PVD, which could help clinicians in the decision-making process from adjusting ventilator settings to deeply sedate or paralyze the patient. Clearly, further studies are needed addressing risk factors, physiologic mechanisms and direct consequences of PVD in order to help clinicians to design effective and proven strategies at the bedside., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pulmonary function testing (PFT) is an important component for evaluating the outcome of experimental rodent models of respiratory diseases. Respiratory inductance plethysmography (RIP) provides a noninvasive method of PFT requiring minimal cooperation. RIP measures work of breathing (WOB) indices including phase angle (Ф), percent rib cage (RC %), breaths per minute (BPM), and labored breathing index (LBI) on an iPad. The aim of this study was to evaluate the utility of a recently developed research instrument, pneuRIP, for evaluation of WOB indices in a developmental rat model. Sprague Dawley rats (2 months old) were commercially acquired and anaesthetised with isoflurane. The pneuRIP system uses two elastic bands: one band (RC) placed around the rib cage under the upper armpit and another band (AB) around the abdomen. The typical thoracoabdominal motion (TAM) plot showed the abdomen and rib cage motion in synchrony. The plots of phase angle and LBI as a function of data point number showed that values were within the range. The distribution for phase angle and LBI was within a narrow range. pneuRIP testing provided instantaneous PFT results. This study demonstrated the utility of RIP as a rapid, noninvasive approach for evaluating treatment interventions in the rodent model.

We previously reported that maternal cigarette smoke (CS) exposure resulted in impairment of central chemoreception and induced mitochondrial dysfunction in offspring parafacial respiratory group (pFRG), the kernel for mammalian central chemoreception. We also found that hydrogen sulfide (H2S) could attenuate maternal CS exposure-induced impairment of central chemoreception in the rat offspring in vivo. Mitochondrial ATP sensitive potassium (mitoKATP) channel has been reported to play a significant role in mitochondrial functions and protect against apoptosis in neurons. Thus, we hypothesize here that mitoKATP channel plays a role in the protective effects of H2S on neonatal central chemoreception in maternal CS-exposed rats. Our findings revealed that pretreatment with NaHS (donor of H2S, 22.4mM) reversed the central chemosensitivity decreased by maternal CS exposure, and also inhibited cell apoptosis in offspring pFRG, however, 5-HD (blocker of mitoKATP channels, 19mM) attenuated the protective effects of NaHS. In addition, NaHS declined pro-apoptotic proteins related to mitochondrial pathway apoptosis in CS rat offspring pFRG, such as Bax, Cytochrome C, caspase9 and caspase3. NaHS or 5-HD alone had no significant effect on above indexes. These results suggest that mitoKATP channels play an important role in the protective effect of H2S against impairment of central chemoreception via anti-apoptosis in pFRG of rat offspring exposed to maternal CS., Competing Interests: The authors have declared that no competing interests exist.

PK20M (Dmt-D-Lys-Phe-Phe-OH) is a novel modified endomorphin-2 (EM-2) peptide producing strong dose- and time-dependent antinociceptive activity. Yet its prototype, endogenous EM-2, has been reported to trigger respiratory and vascular effects such as apnea and hypotension. The purpose of this study was to investigate the potency of the PK20M to evoke respiratory and cardiovascular responses in comparison to endogenous endomorphins. The engagement of the vagal pathway and μ opioid receptors in mediation of these responses was investigated. The effects of intravenous injections of PK20M, EM-1, and EM-2 were studied in anaesthetized, spontaneously breathing rats. The main dose-dependent effect of all endomorphins in the intact rats was immediate apnea, blood pressure and heart rate decrease. PK20M produced apnea in at least half of the intact animals in a much smaller dose than EM-1 and EM-2. The effects of all compounds were abrogated by pre-treatment with MNLX, a peripherally acting μ receptor antagonist. Cervical vagotomy eliminated arrest of breathing in the case of each tested compound. Hypotension was reduced by vagi section only after EM-1 and EM-2 administration. Our results demonstrated that apnea and bradycardia caused by systemic injection of all endomorphins were mediated via activation of μ vagal opioid receptors. The hypotension depended on intact vagi nerves only in the case of EM-1 and EM-2, whereas PK20M decreased blood pressure via other mechanisms outside vagal innervation. Modified opioid agonist is more potent in evoking extended hypotension; at the same time, it produces an arrest of breathing less frequently than its prototype EM-2., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Interscalene brachial plexus block (ISB) provides excellent analgesia for arthroscopic shoulder surgeries but is associated with adverse effects including hemidiaphragmatic paresis. We aimed to compare the respiratory effects, forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) between suprascapular nerve block (SSB) and ISB., Methods: Sixty patients were recruited and randomized into ISB, anterior SSB, and posterior SSB groups. FVC, FEV1, and diaphragmatic excursion were evaluated at baseline and 30 minutes after intervention. Blocks were performed under ultrasound guidance with 15 ml of 0.5% ropivacaine. Pain scores were assessed at 6, 12, and 24 hours postoperatively., Results: The ISB group showed a reduced FVC of 31.2% ± 17.5% (mean ± SD), while the anterior and posterior SSB groups had less reduction of 3.6% ± 18.6% and 6.8% ± 6.5%, respectively (P < 0.001). The ISB group showed more reduction in diaphragmatic excursion than the anterior and posterior SSB groups (median [IQR]): -85.7% (-95.3% to -63.3%) vs. -1.8% (-13.1% to 2.3%) and -1.2% (-8.8% to 16.8%), respectively (P < 0.001). The median pain scores (IQR) in the ISB and anterior SSB groups were lower than those in the posterior SSB group at 6 hours on movement: 0 (0-2), 1.8 (0-4.5) vs. 5 (2.5-8), respectively (P = 0.002). There was no significant difference in oxycodone consumption postoperatively., Conclusions: Anterior SSB preserves lung function and has a comparable analgesic effect as ISB. Thus, it is recommended for arthroscopic shoulder surgeries, especially in patients who have reduced lung function.

Perinatal exposure to drugs of abuse, including alcohol (ethanol), is known to impinge the development of respiratory function. However, most studies described the short-term effects of these exposures, focusing mostly on the early postnatal life. After exposure to ethanol during gestation and lactation we have previously shown that 3-4 week-old rat exhibit chronic hypoventilation and an altered response to hypoxia at the end of ethanol exposure. However, whether these deficits are reversible following ethanol withdrawal remained unknown. Here, we investigated through whole-body plethysmography the respiratory activity of 2 months-old rats exposed to ethanol from gestation to weaning followed by one month of ethanol withdrawal. After ethanol withdrawal, rats persistently exhibited a significant reduction in respiratory frequency without change in tidal volume associated to a lower arterial blood oxygen content. In addition, the response to hypoxia in these rats was reduced whereas the response to hypercapnia remained unaltered. In conclusion perinatal exposure to ethanol in rats, unlike exposure to cocaine, morphine or nicotine, is characterized by selective alterations of basal respiratory activity and chemosensitivity that persist long after withdrawal., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of this study is to compare changes in breathing patterns elicited by hypoxic stress and/or anesthetic stress in mice. Spontaneously breathing anesthetized mice whose tracheae were intubated with a tracheal cannula were challenged with hypoxic stress and/or sevoflurane-induced anesthetic stress while ventilation was measured with a pneumotachograph. When anesthesia was maintained at a light level with inhalation of 2.3 % sevoflurane (0.7 MAC), exposure to severe hypoxic gas (5% O 2 in N 2 ) triggered a breathing pattern characterized by gasping respiration. Inhalation of a high concentration of sevoflurane (6.5 %: 2.0 MAC) under hyperoxia elicited the same gasping. Also, the combination of mild hypoxia (inhalation of 10 % O 2 in N 2 ) and moderate sevoflurane anesthesia (3.25 %: 1.0 MAC) consistently elicited the same gasping, while mild hypoxic and moderate anesthetic stress alone did not elicit any gasping. These findings suggest that both hypoxia-induced gasping and sevoflurane-induced gasping could be generated by the same intrinsic mechanism within the brainstem., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

One of the possible causes of death in epilepsy is breathing disorders, especially apneas, which lead to an increase in CO 2 levels (hypercapnia) and/or a decrease in O 2 levels in arterial blood (hypoxemia). The respiratory neurons located in the ventral brainstem respiratory column are the main groups responsible for controlling breathing. Recent data from our group demonstrated respiratory changes in two experimental models of epilepsy, i.e. audiogenic epilepsy, and amygdala rapid kindling. Here, we aimed to evaluate respiratory changes in the classic model of temporal lobe epilepsy induced by intra-hippocampal injection of pilocarpine. Adult Wistar rats with stainless-steel cannulas implanted in the hippocampus region were used. The animals were submitted to pilocarpine injection (2.4 mg/μL, N = 12-15) or saline (N = 9) into the hippocampus. The respiratory parameters analyzed by whole-body plethysmography were respiratory rate (f R ), tidal volume (V T ) and ventilation (V E ). Respiratory mechanics such as Newtonian airway resistance (R n ), viscance of the pulmonary parenchyma (G) and the elastance of the pulmonary parenchyma (H) were also investigated. No changes in baseline breathing were detected 15 or 30 days after pilocarpine-induced status epilepticus (SE). However, 30 days after pilocarpine-induced SE, a significant reduction in V E was observed during hypercapnic (7% CO 2 ) stimulation, without affecting the hypoxia (8% O 2 ) ventilatory response. We also did not observe changes in respiratory mechanics. The present results suggest that the impairment of the hypercapnia ventilatory response in pilocarpine-induced SE could be related to a presumable degeneration of brainstem respiratory neurons but not to peripheral mechanisms., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Breathing resumes within one to two minutes following fentanyl overdose induced apnea in spontaneously breathing rats. As this regular rhythm is produced at a time wherein fentanyl concentrations and receptor occupancy are likely to be extremely high, the mechanisms initiating and sustaining such a respiratory activity remain unclear. Forty-four un-anesthetized adult rats were studied in an open-flow plethysmograph. Regardless of the dose of fentanyl that was used, i.e. 50 μg.kg -1 (n = 8), 100 μg.kg -1 (n = 8) or 300 μg.kg -1 (n = 7), all rats developed an immediate central apnea followed by a depressed regular rhythm that was produced 118, 97 and 81 s (median) later, respectively. Only one rat did not recover. This inspiratory and regular activity consisted of a low frequency and tidal volume pattern with a significant reduction in V̇E/V̇CO2 ratio, which persisted for at least 30 min and that was not different between 100 or 300 μg.kg -1 . The time at which this respiratory rhythm emerged, following the highest dose of fentanyl, was not affected by 100 % O 2 or 8% CO 2 /15 % O 2 . The absolute level of ventilation was however higher in hypercapnic and moderately hypoxic conditions than in hyperoxia. When a second injection of the highest dose of fentanyl (300 μg.kg -1 ) was performed at 10 min, ventilation was not significantly affected and no apnea was produced in major contrast to the first injection. When a similar injection was performed 30 min after the first injection, in a separate group of rats, an apnea and breathing depression was produced in 30 % of the animals, while in the other rats, ventilation was unaffected. We conclude that the depressed regular respiratory activity emerging during and following fentanyl overdose is uniquely resistant to fentanyl., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%), moderate (60%), and severe (80%) oxygen to determine how hyperoxia-induced changes in lung structure impact pulmonary mechanics in mice., Methods: C57BL/6J mice were exposed to room air or hyperoxia from birth through postnatal day 8. Baseline pulmonary function and methacholine challenge was assessed at 4 and 8 weeks of age, accompanied by immunohistochemical assessments of both airway (smooth muscle, tethering) and alveolar (simplification, elastin deposition) structure., Results: Mild/moderate hyperoxia increased baseline airway resistance (40% only) and airway hyperreactivity (40 and 60%) at 4 weeks accompanied by increased airway smooth muscle deposition, which resolved at 8 weeks. Severe hyperoxia increased baseline compliance, baseline resistance, and total elastin/surface area ratio without increasing airway hyperreactivity, and was accompanied by increased alveolar simplification, decreased airway tethering, and changes in elastin distribution at both time points., Conclusions: Mild to moderate hyperoxia causes changes in airway function and airway hyperreactivity with minimal parenchymal response. Severe hyperoxia drives its functional changes through alveolar simplification, airway tethering, and elastin redistribution. These differential responses can be leveraged to further develop hyperoxia mouse models.

Background: The ventilation/perfusion mismatch in chronic obstructive pulmonary disease (COPD) patients can exacerbate cardiac function as well as pulmonary oxygenation. We hypothesized that inhaled iloprost can ameliorate pulmonary oxygenation with lung mechanics and myocardial function during one-lung ventilation (OLV) in COPD patients combined with poor lung oxygenation., Methods: A total of 40 patients with moderate to severe COPD, who exhibited the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FIO2) <150 mm Hg 30 minutes after initiating OLV, were enrolled in this study. Patients were randomly allocated into either ILO group (n = 20) or Control group (n = 20), in which iloprost (20 μg) and saline were inhaled, respectively. The PaO2/FIO2 ratio, dead space, dynamic compliance, and tissue Doppler imaging with myocardial performance index (MPI) were assessed 30 minutes after initiating OLV (pre-Tx) and 30 minutes after completion of drug inhalation (post-Tx). Repeated variables were analyzed using a linear mixed-model between the groups., Results: At pre-Tx, no differences were observed in measured parameters between the groups. At post-Tx, PaO2/FIO2 ratio (P < .001) and dynamic compliance (P = .023) were significantly higher and dead space ventilation was significantly lower (P = .001) in iloprost group (ILO group) compared to Control group. Left (P = .003) and right ventricular MPIs (P < .001) significantly decreased in ILO group compared to Control group., Conclusions: Inhaled iloprost improved pulmonary oxygenation, lung mechanics, and cardiac function simultaneously during OLV in COPD patients with poor lung oxygenation.

Ethnopharmacological Relevance: Pequi fruit are obtained from the pequi tree (Caryocar coriaceum), from which the pulp and nut are used in order to extract an oil that is commonly used in popular medicine as an antiinflammatory agent, particularly for the treatment of colds, bronchitis and bronchopulmonary infections. Making use of the fixed oil of Caryocar coriaceum (FOCC), an attractive alternative for the treatment of diseases caused by exposure to environmental tobacco smoke., Aim of the Study: To evaluate whether oral intake FOCC provides beneficial effects in the respiratory system of rats submitted to a short-term secondhand smoke (SHS) exposure model., Materials and Methods: The experiments were performed on Wistar rats divided into 4 groups; in the SHS + O and SHS + T groups, the animals were pretreated orally with 0.5 mL of FOCC (SHS + O) or vehicle (Tween-80 [1%] solution) (SHS + T). Immediately after pretreatment, the animals were submitted to the SHS exposure protocol, for a total period of 14 days. Exposures were performed 6 times per day, with a duration of 40 min per exposure (5 cigarettes per exposure), followed by a 1-h interval between subsequent exposures. In the AA + O and AA + T groups, animals were submitted to daily oral pretreatment with 0.5 mL of FOCC (AA + O) or vehicle (AA + T). These animals were then subjected to the aforementioned exposure protocol, but using ambient air. After the exposure period, we investigated the effects of FOCC in respiratory mechanics in vivo (Newtonian resistance -R N , tissue elastance -H, tissue resistance -G, static compliance -C ST , inspiratory capacity -IC, PV loop area) histopathology and lung parenchymal morphometry in vitro (polymorphonuclear cells -PMN, mean alveolar diameter -L m , bronchoconstriction index -BCI), temporal evolution of subjects' masses, and percent composition of the FOCC., Results: Regarding the body mass of the animals, the results demonstrated an average body mass gain of 10.5 g for the animals in the AA + T group, and 15.5 g for those in the AA + O group. On the other hand, the body mass of animals in the SHS + T and SHS + O suffered an average loss of 14.4 and 4.75 g, respectively. Regarding respiratory system analyzes, our results demonstrated significant changes in all respiratory mechanics variables and lung parenchyma morphometry analyzed for the SHS + T group when compared to the AA + T group (p < 0,05), confirming the establishment of pulmonary injury induced by SHS exposure. We also observed that rats pretreated orally with FOCC (SHS + O) showed improvement in all variables when compared to the SHS + T group (p < 0,05), thus demonstrating the effectiveness of FOCC in preventing lung damage induced by short-term SHS exposure., Conclusion: In conclusion, our results demonstrate that FOCC was able to prevent lung injury in rats submitted to short-term SHS exposure., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interests regarding the publication of this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Swimming is one of the most popular forms of physical activity. Pool water is cleaned with chlorine, which - in combination with compounds contained in water - could form chloramines and trichloromethane in the swimmer's lungs. The aim of the present study was to examine the effect of swimming training in an indoor pool on the composition of swimmers' respiratory phase metabolomics, and develop a system to provide basic information about its impact on the swimmer's airway mucosa metabolism, which could help to assess the risk of secondary respiratory tract diseases i.e. sport results, condition, and health including lung acute and chronic diseases)., Design: A group of competitive swimmers participated in the study and samples of their respiratory phase before training, immediately after training, and 2 h after training were assessed., Methods: Sixteen male national and international-level competitive swimmers participated in this study. Respiratory phase analysis of the indoor swimming pool swimmers was performed. Gas chromatography combined with mass spectrometry (GCMS) was used in the measurements. All collected data were transferred to numerical analysis for trends of tracking and mapping. The breathing phase was collected on special porous material and analyzed using GCMS headspace., Results: The obtained samples of exhaled air were composed of significantly different metabolomics when compared before, during and after exercise training. This suggests that exposition to indoor chlorine causes changes in the airway mucosa., Conclusion: This phenomenon may be explained by occurrence of a chlorine-initiated bio-reaction in the swimmers' lungs. The obtained results indicate that chromatographic exhaled gas analysis is a sensitive method of pulmonary metabolomic changes assessment. Presented analysis of swimmers exhaled air indicates, that indoor swimming may be responsible for airway irritation caused by volatile chlorine compounds and their influence on lung metabolism.

Purpose: The aim of this study was to compare tracheal intubation conditions after induction of anesthesia with a bolus of propofol-sufentanil or propofol-remifentanil and a rapid induction technique., Material and Methods: A total of 70 patients (American Society of Anesthesiologists (ASA) classification I‑II) undergoing outpatient surgery under general anesthesia with intubation for tooth extraction were randomly assigned to two groups in this double-blind study. Patients received either a bolus of remifentanil (3 μg/kg) or sufentanil (0.3 μg/kg) together with 2.5 mg/kg propofol for intubation. The primary outcome was the percentage of excellent intubation conditions and the secondary outcomes were the percentage of patients with a decrease of over 20% in mean arterial pressure (MAP) or heart rate (HR), time to achieve spontaneous respiration, time between the end of surgery and extubation and time to achieve an Aldrete score of 10. VAS pain score was >3 or having laryngeal pain 15 min after arriving in the postanesthesia care unit (PACU) were also analyzed., Results: Intubating conditions (perfect + good conditions) were significantly better with remifentanil than with sufentanil (88.5% vs. 68.6%; p = 0.01). When using remifentanil, the hemodynamic conditions were good. Using remifentanil did not significantly increase the pain score or the laryngeal pain in the recovery room. This was confirmed by no significant differences between the groups for morphine consumption. Remifentanil significantly decreased the time to achieve an Aldrete score of 10., Conclusion: When intubation without muscle relaxants is required, intubating conditions are much better when a remifentanil bolus is used compared to a sufentanil bolus. The remifentanil/propofol rapid induction technique is a valuable technique to quickly intubate and achieve good conditions.

Rationale and Objectives: The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration)., Results: BBI-11008 had a 78-fold greater affinity for the delta opioid receptor than the mu receptor, and there was no binding to the kappa opioid receptor. BBI-11008 (3.2-100; 10-32 mg kg -1 , i.v.) and morphine (1-10; 1-3.2 mg kg -1 , i.v.) produced antinociceptive and anti-allodynic effects in assays of acute thermal nociception and complete Freund's adjuvant (CFA)-induced inflammatory pain, with BBI-11008 being less potent than morphine in both assays. BBI-11008 (1-18 mg kg -1 , i.v.) had similar efficacy to gabapentin (10-56 mg kg -1 , i.v.) in a spinal nerve ligation (SNL) model of neuropathic pain. In the respiration assay, with increasing %CO 2 exposure, BBI-11008 produced an initial increase (32 mg kg -1 , s.c.) and then decrease (56 mg kg -1 , s.c.) in minute volume (MV) whereas morphine (3.2-32 mg kg -1 , s.c.) produced dose-dependent decreases in MV. In the drug self-administration procedure, BBI-11008 did not maintain self-administration at any dose tested., Conclusions: These results suggest that the glycopeptide drug candidate possesses broad-spectrum antinociceptive and anti-allodynic activity across a range of pain-like conditions. Relative to morphine or fentanyl, the profile for BBI-11008 in the respiration and drug self-administration assays suggests that BBI-11008 may have less pronounced deleterious side effects. Continued assessment of this compound is warranted.

Background: Cigarette smoke is the major cause of airway inflammatory disease, including airway hyperresponsiveness. Eucalyptol (EUC), also named 1.8-cineole, is a monoterpenoid found in essential oil of medicinal plants, showing several biological effects., Hypothesis/purpose: Based in the eucalyptol protective activity in respiratory diseases as asthma, our hypothesis is that eucalyptol is able to reduce the airway hyperresponsiveness and the respiratory mechanic parameters in rats exposed to cigarette smoke., Study Design: Wistar rats were divided into control and cigarettes smoke (CS) groups. CS group was daily subjected to cigarette smoke and treated by inhalation for 15 min/day with EUC (1 mg/mL) or vehicle during 30 days. After treatment, bronchoalveolar lavage (BAL) was collected to analyze the inflammatory profile, and tracheal rings were isolated for evaluation of the airway smooth muscle hyperresponsiveness. Lung function was analyzed in vivo., Methods: The inflammatory profile was evaluated by optical microscopy performing total (Neubauer chamber) and differential leukocyte count (smear slides stained in H&E). The hyperresponsiveness was evaluated in tracheal rings contracted with potassium chloride (KCl) carbamoylcholine (CCh), or Barium chloride (BaCl 2 ) in presence or absence of nifedipine. The lung function (Newtonian resistance-R N ) was evaluated by bronco stimulation with methacholine (MCh)., Results: BAL from CS group increased the influx of leukocyte, mainly neutrophils and macrophages compared to control group. EUC reduced by 71% this influx. The tracheal contractions induced by KCl, CCh or BaCl 2 were reduced by EUC in 59%, 42% and 26%, respectively. The last one was not different of nifedipine activity. Newtonian resistance (R N ) was also reduced in 37% by EUC compared to CS group. 
 CONCLUSION: EUC reduces the hyperresponsiveness and the airway inflammatory profile, recovering the lung function., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2020. Published by Elsevier Ltd.)

Pulmonary drug delivery has gained great interest as an important subject of research over the past decades given the lung diseases which are affecting millions of people suffer from these diseases. Drug delivery into the respiratory system is influenced by many anatomical and physiological factors such as lung morphometry, breathing patterns, fluid dynamics, particle properties, etc. The respiratory airway structure is one of these parameters which greatly influences the deposition pattern of inhaled drug particles. There have been a wide variety of major morphometric studies, conducted using cadavers to increase an understanding of the respiratory airway anatomy and provide important information for developing realistic airway models. Casting as one of the first methods, was utilized for morphometric studies providing a hollow model for in vitro investigations. The above-mentioned morphometric data were utilized to describe the first idealized airway model as a simple symmetric description of the branching airways, later followed by more realistic asymmetric models. However, even these asymmetric airway models were not good enough to reflect the anatomical complexities of the human respiratory airway and contained several major limitations which made them inefficient. Further attempts alongside with the progress of technology led to introduction of the stochastic and image-based models which provided more realistic and efficient tools for numerical and experimental investigations. The main objective of this study is to provide a comprehensive review about the development of different perspectives of the respiratory airway modeling over the past decades. The following sections will present useful information about anatomy of the human respiratory tract, and different viewpoints of the respiratory airway modeling, including their historical routes, strengths, and deficiencies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

As stated by Korpáš and Tomori (1979), cough is the most important airway protective reflex which provides airway defensive responses to nociceptive stimuli. They recognized that active expiratory efforts, due to the activation of caudal ventral respiratory group (cVRG) expiratory premotoneurons, are the prominent component of coughs. Here, we discuss data suggesting that neurons located in the cVRG have an essential role in the generation of both the inspiratory and expiratory components of the cough reflex. Some lines of evidence indicate that cVRG expiratory neurons, when strongly activated, may subserve the alternation of inspiratory and expiratory cough bursts, possibly owing to the presence of axon collaterals. Of note, experimental findings such as blockade or impairment of glutamatergic transmission to the cVRG neurons lead to the view that neurons located in the cVRG are crucial for the production of the complete cough motor pattern. The involvement of bulbospinal expiratory neurons seems unlikely since their activation affects differentially expiratory and inspiratory muscles, while their blockade does not affect baseline inspiratory activity. Thus, other types of cVRG neurons with their medullary projections should have a role and possibly contribute to the fine tuning of the intensity of inspiratory and expiratory efforts.

Nebulization with saline solution, although commonly used to alleviate respiratory symptoms, particularly in children, is often questioned concerning its effectiveness. In this study, we investigated the effects of isotonic saline nebulization on lung function in 40 children (mean age of 14±1 years) suffering from different types of airway disorders. Measurements were carried out directly before and up to 15 min after nebulization, for six days in a row, always on the same day time in the morning. The children were divided into two study groups according to the baseline ratio of forced expired volume in one second/forced vital capacity (FEV1/FVC), below and above 80 %. We found significant improvements after saline nebulization in FEV1, mid-expiratory flow at 50 % and 75 % of FVC (MEF50 and MEF75), and peak expiratory flow (PEF) in the group with the baseline FEV1/FVC less than 80 %. In contradistinction, children with an index greater than 80 % displayed no appreciable changes in the lung function variables when compared with the baseline level before saline nebulization. We conclude that isotonic saline nebulization might mitigate the functional signs of threatening pulmonary obstruction and as such may be clinically useful in pediatric patients with mild respiratory problems.

Background: Our study aimed to compare the effects of Sevoflurane- and propofol-based anaesthetic regimens on oxygenation during the early period of cardiopulmonary bypass (CPB) in patients undergoing cardiac valve-replacement surgery., Methods: Patients undergoing mechanical mitral, aortic or double valve replacement were enrolled and randomly divided into two groups: the sevoflurane-based anaesthetic regimen group consisted of patients who received 1-3% sevoflurane inhalation during anaesthesia maintenance and the propofol-based anaesthetic regimen group consisted of patients who received 6-10 mg/kg/h of propofol infusion during anaesthesia maintenance. The partial pressure of oxygen/fraction of inspired oxygen (PaO 2 /FiO 2 ), respiratory mechanics and haemodynamics were recorded during CPB., Results: Forty-two patients met the eligibility criteria for the study. The groups did not differ in terms of clinical and demographic characteristics, and pre- and intra-operative features. Changes in oxygenation were mild (mean PaO 2 /FiO 2 from 358 ± 82 to 471 ± 106 mmHg) within one hour of CPB in our patients. There were no differences in PaO 2 /FiO 2 , respiratory mechanics and haemodynamics between the sevoflurane and propofol groups., Conclusions: In patients undergoing cardiac valve replacement with CPB, lung injury was mild, and sevoflurane- and propofol-based anaesthetic regimens showed similar effect on oxygenation, respiratory mechanics and haemodynamics during the early stage of CPB.

Mammals airways are extensively innervated by the vagus nerve, which controls the airway diameter and bronchial tone. However, very few studies described the respiratory function and lung morphology after vagal section. In the present study, we evaluated the respiratory mechanics after aerosolization of vehicle (to obtain control values), a muscarinic agonist (methacholine), a β 2 -adrenergic agonist (salbutamol) or a muscarinic antagonist (ipratropium bromide) in intact (Vi) and bilaterally vagotomized (Vx) Swiss male mice. Different group was established for morphometric analyze. The total lung resistance, airway resistance, elastance, compliance, lung tissue damping, lung tissue elastance, and morphological parameters (collagen and elastic fibers) were significantly different in the Vx group compared to the Vi group. Bronchoconstrictor and bronchodilators change the respiratory function of the Vx group. In conclusion, the vagus nerve modulates the lung function in response to bronchoconstriction and bronchodilation, as well as lung architecture of mice., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2019. Published by Elsevier B.V.)

Aim: This study aimed to analyze the Constant Phase Model (CPM) Coefficient of Determination (COD) and an index of harmonic distortion ([Formula: see text]) behavior in intravenous methacholine dose response curve. We studied the COD and [Formula: see text] behavior of Control and Lung Inflammation (OVA) groups of mice and we proposed an alternative for moments when the CPM should not be applied. Methods: 9-week female BALB/c mice were studied, 8 of the control group (23.11 ± 1.27 g) and 11 of the lung inflammation group (OVA) (21.45 ± 2.16 g). The COD values were obtained during the respiratory mechanics assessment via Forced Oscillation Technique (FOT) and the [Formula: see text] was estimated a posteriori. Both control and OVA groups were submitted to 4 doses of Methacholine (MCh) protocol. Results: A strong correlation between COD and [Formula: see text] was present at the last two doses (0.3 mg/kg: r = -0.75, p  = 0.0013 and 1 mg/kg: r = -0.91; p  < 0.0001) in the OVA group. Differences were found in doses of 0.3 mg/kg between control and OVA for the maximum values of Rn (Newtonian Resistance) and G (tissue viscous); and between groups at PBS and doses of 0.03, 0.1 and 0.3 mg/kg for H (Elastance). A similar behavior was observed for the analysis of Area Under the Curve with the exclusion of the 3 first measurements of each dose. However, in this scenario, the comparison with the maximum value presented a higher discriminatory capacity of the parameters associated with the parenchyma. Conclusions: During severe bronchoconstriction there is a strong negative correlation between model goodness of fit and nonlinearities levels, reinforcing that COD is a robust acceptance criterion, whether still simple and easily obtained from the ventilator. We also pointed out the area under the CPM parameters dose response curve is a useful and can be used as a complementary analysis to peak comparison following bolus injections of methacholine.

Background: Drug induced sleep endoscopy (DISE) has emerged as a promising tool for customizing the adequate surgical approach to relieve airway obstruction in sleep apnea patients. We aimed to compare propofol, dexmedetomidine or ketofol with regards their efficacy and safety for sedation in patients with obstructive sleep apnea (OSA) undergoing DISE procedure., Methods: Sixty adult OSA patients scheduled for DISE procedure were randomly allocated into three equal groups to receive either propofol (group P), dexmedetomidine (group D), or ketofol (group K). Incidence of oxygen desaturation <90%, hemodynamic variables, time to achieve sufficient sedation level, recovery time, patients' and endoscopists' satisfaction, and incidence of adverse effects were recorded., Results: Higher incidence of oxygen desaturation <90% was observed in group P as compared to groups D and K (70%, 35%, and 30% respectively, P=0.021*). Group D showed a significantly longer time to reach target sedation level, prolonged recovery time with more consumption of rescue propofol as compared to group P and group K (P=0.000*, 0.000*, 0.000* respectively). Heart rate values were lower in group D after the loading dose till 30 min postoperative as compared to the other two groups, while blood pressure was lower in both P and D groups at five, 10, 15 min, and on reaching recovery room compared to K group. Two patients in the K group had psychomimetic symptoms with no difference between groups as regards other adverse events or patients' and endoscopist's satisfactions., Conclusions: Dexmedetomidine and ketofol provided a safe respiratory profile compared to propofol during DISE without significant hemodynamic adverse events.

Background: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol can rapidly reverse tolerance to morphine-induced respiratory depression. However, alcohol consumption by opioid users is likely to occur over prolonged time periods. We have therefore sought to determine the effect of prolonged alcohol consumption on the development of tolerance to opioid respiratory depression., Methods: Mice were fed control or ethanol (5%) liquid diet for 16 days. On days 9-16 morphine tolerance was induced by administration of 3 priming injections of morphine followed by subcutaneous implantation of a morphine-filled osmotic mini-pump. Control mice received saline. Respiration was measured by plethysmography and the effect of an acute morphine challenge dose was measured on day 16 to assess the development of morphine tolerance., Results: Prolonged ethanol consumption for 14 days did not alter the respiratory depressant effect of an acute dose of morphine. Control mice treated with prolonged morphine developed tolerance to acute morphine respiratory depression whereas ethanol diet fed mice treated with prolonged morphine showed significant respiratory depression during morphine-pump treatment and remained sensitive to the respiratory depressant effect of the acute challenge dose of morphine. The ethanol consumption did not alter blood or brain levels of morphine, whilst conversely prolonged morphine treatment did not alter blood levels of ethanol., Conclusions: Prolonged ethanol consumption prevents the development and maintenance of tolerance to the respiratory depressant effect of morphine. These data suggest that ethanol inhibition of tolerance will greatly increase the risk of fatal heroin overdose in humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To compare the effects of sevoflurane, desflurane, and propofol on respiratory mechanics, and integrated pulmonary index (IPI) scores in patients undergoing laparoscopic sleeve gastrectomy., Methods: A total of 60 patients with a body mass index of ≥40 kg/m2, who underwent laparoscopic sleeve gastrectomy between September 2015 and September 2016 at Fatih Sultan Mehmet Health Application and Research Center, Istanbul, Turkey were included in this randomized prospective study. After induction, anesthesia was maintained by sevoflurane in group S, desflurane in group D, and propofol in group P. Peak inspiratory pressure (PIP), plateau pressure (Pplateau), compliance (Cdyn), respiratory resistance (Rrs), and IPI values were recorded. Mann-Whitney U, Kruskal- Wallis, Dunn's, Friedman, and Fisher-Freeman- Halton tests were performed for statistical analysis. A p value of less than 0.05 was considered statistically significant., Results: A significant increase was found in PIP in group S (T1: 25; T2: 27 cmH2O), and group D (T1: 25; T2: 29,5 cmH2O) during pneumoperitoneum. Dynamic compliance decreased in all groups during pneumoperitoneum. In group S, the decrease in Cdyn was also statistically significant after pneumoperitoneum(T1:43.65;T5:41.25ml/cmH2O). Comparison between groups the values of PIP, Pplateau, Cdyn, Rrs, and IPI were similar., Conclusion: In morbidly obese patients, sevoflurane, desflurane, and propofol are similar in terms of the intraoperative respiratory mechanics, and perioperative respiratory parameters provided with IPI.

Objective: To provide a non-invasive approach to monitoring lung function in spontaneously breathing lambs, from birth to five months of life, by the forced oscillation technique (FOT). This report describes the experimental set-up, data processing, and identification of normal predicted values of resistance (Rrs) and reactance (Xrs) of the respiratory system, along with normal bronchodilator response for bronchial reversibility testing., Approach: Rrs and Xrs at 5, 11, and 19 Hz were measured monthly for five months in 20 normal term lambs that breathed spontaneously. In seven lambs, repeated measurements also were made within the first month of life (at 3, 7, 14, and 21 d of life). We determined the repeatability and reproducibility of the measurements and characterized the relationship between lung mechanics and age, sex, and body dimensions, using regression analysis, and measured changes in lung mechanics in response to inhaled bronchodilator., Main Results: The measurements provided repeatable and reproducible data. Rrs decreased, whereas Xrs increased, with growth from birth through the first two months of life, after which no statistically significant differences were detected. We identified normal value equations for Rrs and Xrs and for each of the measured anthropometric variables. Respiratory system mechanics were not affected by the bronchodilator., Significance: The FOT provides reliable non-invasive measurement of respiratory system mechanics in spontaneously breathing term lambs from birth to five months of age. The methods and normal reference values defined in this study will facilitate testing of the pathophysiological consequences of preterm birth and prolonged respiratory support on respiratory system mechanics.

Purpose: Mechanical ventilation is a well-established therapy for patients with acute respiratory failure. However, up to 35% of mortality in acute respiratory distress syndrome may be attributed to ventilation-induced lung injury (VILI). We previously demonstrated the efficacy of the synthetic tripeptide feG for preventing and ameliorating acute pancreatitis-associated lung injury. However, as the mechanisms of induction of injury during mechanical ventilation may differ, we aimed to investigate the effect of feG in a rodent model of VILI, with or without secondary challenge, as a preventative treatment when administered before injury (prophylactic), or as a therapeutic treatment administered following initiation of injury (therapeutic)., Methods: Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a rodent model of ventilation-induced lung injury, with or without secondary intratracheal lipopolysaccharide challenge., Results: Prophylactic feG administration resulted in significant improvements in arterial blood oxygenation and respiratory mechanics, and decreased lung oedema, bronchoalveolar lavage protein concentration, histological tissue injury scores, blood vessel activation, bronchoalveolar lavage cell infiltration and lung myeloperoxidase activity in VILI, both with and without lipopolysaccharide. Therapeutic feG administration similarly ameliorated the severity of tissue damage and encouraged the resolution of injury. feG associated decreases in endothelial adhesion molecules may indicate a mechanism for these effects., Conclusions: This study supports the potential for feG as a pharmacological agent in the prevention or treatment of lung injury associated with mechanical ventilation.

To evaluate whether a recombinant serine protease inhibitor (rBmTI-A) modulates inflammation in an experimental model of chronic allergic lung inflammation. Balb/c mice were divided into four groups: SAL (saline), OVA (sensitized with ovalbumin), SAL + rBmTI-A (control treated with rBmTI-A) and OVA + rBmTI-A (sensitized with ovalbumin and treated with rBmTI-A). The animals received an intraperitoneal injection of saline or ovalbumin, according to the group. The groups received inhalation with saline or ovalbumin and were treated with rBmTI-A or saline by nasal instillation. After 29 days, we evaluated the respiratory mechanics; bronchoalveolar lavage fluid (BALF); cytokines; MMP-9, TIMP-1; eosinophils; collagen and elastic fibre expression in the airways; and the trypsin-like, MMP-1, and MMP-9 lung tissue proteolytic activity. Treatment with rBmTI-A reduced the trypsin-like proteolytic activity, the elastance and resistance maximum response, the polymorphonuclear cells, IL-5, IL-10, IL-13 and IL-17A in the BALF, the expression of IL-5, IL-13, IL-17, CD4+, MMP-9, TIMP-1, eosinophils, collagen and elastic fibres in the airways of the OVA + rBmTI-A group compared to the OVA group (p < 0.05). rBmTI-A attenuated bronchial hyperresponsiveness, inflammation and remodelling in this experimental model of chronic allergic pulmonary inflammation. This inhibitor may serve as a potential therapeutic tool for asthma treatment.

Nesfatin-1, which is an anorexiogenic peptide, plays a crucial role as a neurotransmitter and/or neuromodulator in the central nervous system for cardiovascular control and energy balance etc. It is expressed abundantly in multiple brain nuclei including central respiratory control areas such as nucleus tractus solitarius, nucleus ambiguous, dorsal vagal complex, dorsal motor nucleus of the vagus nerve, and hypothalamus. To date, no previous studies have been found to report nesfatin-1-evoked respiratory effects. Therefore, the present study was designed to investigate the possible impacts of centrally and/or peripherally injected nesfatin-1 on respiratory parameters in either 12h-fasted or fed-ad libitum rats. Intracerebroventricular (ICV) administration of nesfatin-1 provoked significant hyperventilation by increasing tidal volume (TV), respiratory rate (RR) and respiratory minute ventilation (RMV) in both the 12h-fasted and the fed-ad libitum Spraque Dawley rats in dose- and time- dependent manner. Moreover, the hyperventilatory effects of centrally injected nesfatin-1 were more potent in the fed-ad libitum rats. Intravenous injection of nesfatin-1 induced a significant rise in RR and RMV, but not in TV, in the fed-ad libitum rats. In conclusion, these findings plainly report that both centrally and/or peripherally injected nesfatin-1 induces significant hyperventilatory effects in the 12h-fasted and the fed-ad libitum rats. These hyperventilatory effects of nesfatin-1 might show a discrepancy according to the food intake of the rats and the delivery method of the peptide., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ozone causes airway hyperresponsiveness, a defining feature of asthma, and is an asthma trigger. In mice, ozone-induced airway hyperresponsiveness is greater in males than in females, suggesting a role for sex hormones in the response to ozone. To examine the role of androgens in these sex differences, we castrated 4-week-old mice. Controls underwent sham surgery. At 8 weeks of age, mice were exposed to ozone (2ppm, 3 h) or room air. Twenty-four hours later, mice were anesthetized and measurements of airway responsiveness to inhaled aerosolized methacholine were made. Mice were then euthanized and bronchoalveolar lavage was performed. Castration attenuated ozone-induced airway hyperresponsiveness and reduced bronchoalveolar lavage cells. In intact males, flutamide, an androgen receptor inhibitor, had similar effects to castration. Bronchoalveolar lavage concentrations of several cytokines were reduced by either castration or flutamide treatment, but only IL-1α was reduced by both castration and flutamide. Furthermore, an anti-IL-1α antibody reduced bronchoalveolar lavage neutrophils in intact males, although it did not alter ozone-induced airway hyperresponsiveness. Our data indicate that androgens augment pulmonary responses to ozone and that IL-1α may contribute to the effects of androgens on ozone-induced cellular inflammation but not airway hyperresponsiveness., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)