Lung Resistance Research Articles

Investigating the Effect of Expiratory Time Constant on Outcome in Intubated Patients with Acute Respiratory Failure Caused by COVID-19 in Critical Care Unit: A Research Study.

BackgroundThe coronavirus disease 2019 (COVID-19) has a high prevalence and mortality worldwide. Thousands of patients with acute respiratory failure caused by COVID-19 are daily hospitalized in intensive care units (ICUs) around the world. Many of these patients require full mechanical respiratory support and long-term ventilator use. Using different ventilators and calculating important variables can be helpful in meeting therapeutic needs of patients.ObjectivesThe aim of present study was to investigate the effect of expiratory time constant (RCEXP) on the course of treatment and duration of mechanical ventilation in patients with acute respiratory failure hospitalized in ICU.MethodsThe present cross-sectional study was conducted on 60 patients with acute respiratory failure who were hospitalized in the ICU and underwent mechanical ventilation due to COVID-19 in the first six months of 2020. The variables of RCEXP, lung compliance and lung resistance in all patients were recorded daily and analyzed. Then, based on clinical outcome, the patients were divided into two groups: the patients with wean outcome (N = 40) and those with death outcome (N = 20).ResultsThe mean ± SD of lung compliance in patients who were separated from ventilator and patients with death outcome were 74.73 (18.58) mL/cm H2O and 36.92 (10.56) mL/cm H2O, respectively, which was statistically significant (P = 0.001). The mean ± SD of lung resistance in patients who were separated from ventilator and patients with death outcome were calculated at 9.25 (4.62) and 14 (6.5), respectively, which was statistically significant (P = 0.015). Also, there was a statistically significant difference between the two groups in terms of mean ± SD of RCEXP (0.67 (0.23) vs. 0.49 (0.19), P = 0.010).ConclusionsAccording to the results of this study, there was a significant difference between high resistance, low compliance, RCEXP, and weaning success of intubation in patients hospitalized in the ICU.

'Silymarin' a Potential Treatment Targeting Hepatic Fibrosis of Schistosomiasis

Background: Despite all treatment and control efforts, schistosomiasis still thrives in humanity. It is endemic in 78 countries that are anchored by poverty and diseases. Until now, the broad-spectrum praziquantel (PZQ) drug is the only effective treatment of choice. However, reports documented some side effects for PZQ like haemorrhage in lung tissues, resistance, and inefficacy to treat fibrotic tissues. Therefore, alternative drugs that help in reducing the undesired effects of schistosomiasis are required. This study examined the efficacy of Silymarin in interfering with the fibrogenesis process using a mouse model. Silymarin is a herbal extract known to have flavonoids and polyphenols that help in reducing the inflammatory reaction, stimulating hepatocyte regeneration, and inhibiting the fibrogenesis process.
 Methods: A total of thirty adult tBALB/c male mice were divided into negative, chronically infected control and treated groups. All were killed after 18 weeks from the initial infection. Different histopathological investigations and liver function tests were carried out to detect the difference between the groups.
 Results: Administration of Silymarin exhibited a significant improvement in all associated histopathology with a considerable decline in the area percentage of collagen fibers. It restored the elevated level of serum ALT as well.
 Conclusion: Silymarin as a treatment for chronic hepatopathies will only be successful if started during the acute phase of the disease.

Upper airway symptoms and Small Airways Disease in Chronic Obstructive Pulmonary Disease, COPD

BackgroundSmall Airways Disease (SAD) is a recognised part of the pathology in Chronic Obstructive Pulmonary Disease (COPD) and contributes to the symptom burden in the disease. Upper airway symptoms in COPD is an emerging field of study, and in this study, we sought to examine the co-existence of SAD and upper airways symptoms in a cohort of COPD patients MethodsWe investigated a cohort of patients with COPD for the presence of SAD with three different modalities. We performed High-Resolution CT (HRCT) with Parametric Response Mapping (PRM) analysis and recorded distribution of emphysema (PRMEmph) and functional Small Airways Disease (PRMfSAD). We measured central and peripheral lung resistance using Impulse Oscillometry (IOS) and recorded R5Hz, R20Hz, R5-R20Hz, X5, Fres and Ax. Static lung function parameters were obtained using Body Plethysmography.Data on upper and lower airway symptoms were evaluated using the Upper Airway subdomain of the 22 items Sino Nasal Outcome Test (SNOT22nasal) and the COPD Assessment Test (CAT), respectively. FindingsWe recruited a total of 112 patients. (female sex: 58%, Age 68 (±8) years, FEV1%predicted: 53% (±16%), GOLD stage: A: 23%, B: 55%, C:1% D: 21%). Forty-five (40%) were classified as having high upper airway symptoms (UAS), defined as SNOT22nasal ≥6. Eighty-seven per cent showed signs of SAD using IOS (R5-R20Hz > 0.07 kPa/L/s). No significant differences were found between UAS groups in IOS, PRM or Body Plethysmography parameters. ConclusionIn patients with COPD, the prevalence of small airways disease was very high, but no association between upper airway symptoms and small airways disease was demonstrated.

PM2.5 induces airway hyperresponsiveness and inflammation via the AhR pathway in a sensitized Guinea pig asthma-like model

Exposure to fine particulate matter (PM2.5) induces airway inflammation and hyperreactivity that lead to asthma. The mechanisms involved are still under investigation. We investigated the effect of resveratrol (3,4’,5-trihydroxystilbene) (RES) on airway hyperresponsiveness, inflammation and CYP1A1 protein expression (an aryl hydrocarbon receptor (AhR) target) induced by PM2.5 exposure in an allergic asthma experimental guinea pig model. The polyphenolic compound RES was used due to its antioxidant and anti-inflammatory properties and as an antagonist of the AhR; thus, providing mechanistic insights.Animals were sensitized with aluminum hydroxide and ovalbumin and exposed to filtered air or PM2.5. Exposure to PM2.5 was conducted using a whole-body chamber particle concentrator (5 h/day) for 15 days. Animals received saline solution or RES (10 mg/kg per day) orally for 21 days simultaneously to the OVA challenge or PM2.5 exposure.PM2.5 exposure (mean 433 ± 111 μg/m3 in the exposure chamber) in OVA challenged animals induced an asthma-like phenotype characterized by increased baseline lung resistance (Rrs) and central airway resistance (Rn) in response to acetylcholine (ACh) evaluated using a flexiVent system®. A parallel increase of pro-inflammatory cytokines (IL-6, IL-17, TNF-α and IFN-γ), inflammatory cells (eosinophils and neutrophils) in bronchoalveolar lavage fluid (BALF) and lung CYP1A1 increase also occurred. RES significantly inhibited airway hyperresponsiveness, inflammation, and CYP1A1 protein expression in the OVA-challenged PM2.5 exposed animals.In summary, with the use of RES we demonstrate that PM-induced airway hyperreactivity is modulated by the inflammatory response via the AhR pathway in an allergic asthma guinea pig model.

STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration.

Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.

Diesel exhaust exposure in mice induces pulmonary fibrosis by TGF-β/Smad3 signaling pathway

BackgroundEpidemiological studies suggest increased risk of lung cancer associated with diesel exhaust (DE) exposure. However, DE-induced lung fibrosis may lead to cancer and needs investigation. ObjectivesTo study the mechanism involved in the initiation of DE- induced lung fibrosis. MethodsC57BL/6 mice were exposed to DE for 30 min/day for 5 days/weeks for 8 weeks. Pulmonary function test was performed to measure lung function. Mice were euthanized to collect BALF, blood, and lung tissue. BALF was used for cell count and cytokine analysis. Lung tissue slides were stained to examine structural integrity. RNA from lung tissue was used for RT-PCR. Immunoblots were performed to study fibrosis and EMT pathway. ResultsMice exposed to DE increase lung resistance and tissue elastance with decrease in inspiratory capacity (p < 0.05) suggesting lung function impairment. BALF showed significantly increased macrophages, neutrophils and monocytes (p < 0.01). Additionally, there was an increase in inflammation and alveolar wall thickening in lungs (p < 0.01) correlates with cellular infiltration. Macrophages had black soot deposition in lung tissue of DE exposed mice. Lung section staining revealed increase in mucus producing goblet cells for clearance of soot in lung. DE exposed lung showed increased collagen deposition and hydroxyproline residue (p < 0.01). Repetitive exposure of DE in mice lead to tissue remodeling in lung, demonstrated by fibrotic foci and smooth muscles. A significant increase in α-SMA and fibronectin (p < 0.05) in lung indicate progression of pulmonary fibrosis. TGF-β/Smad3 signaling was activated with increase in P-smad3 expression in DE exposed mice. Decreased expression of E-cadherin and increased vimentin (p < 0.05) in lungs of DE exposed mice indicate epithelial to mesenchymal transition. ConclusionDE exposure to mice induced lung injury and pulmonary fibrosis thereby remodeling tissue. The study demonstrates TGF-β/SMAD3 pathway involvement with an activation of EMT in DE exposed mice.

RNF8-mediated regulation of Akt promotes lung cancer cell survival and resistance to DNA damage.

Despite the tremendous success of targeted and conventional therapies for lung cancer, therapeutic resistance is a common and major clinical challenge. RNF8 is a ubiquitin E3 ligase that plays essential roles in the DNA damage response; however, its role in the pathogenesis of lung cancer is unclear. Here, we report that RNF8 is overexpressed in lung cancer and positively correlates with the expression of p-Akt and poor survival of patients with non-small-cell lung cancer. In addition, we identify RNF8 as the E3 ligase for regulating the activation of Akt by K63-linked ubiquitination under physiological and genotoxic conditions, which leads to lung cancer cell proliferation and resistance to chemotherapy. Together, our study suggests that RNF8 could be a very promising target in precision medicine for lung cancer.

Evaluation of Lung Aeration and Respiratory System Mechanics in Obese Dogs Ventilated With Tidal Volumes Based on Ideal vs. Current Body Weight.

We describe the respiratory mechanics and lung aeration in anesthetized obese dogs ventilated with tidal volumes (VT) based on ideal (VTi) vs. current (VTc) body weight. Six dogs with body condition scores ≥ 8/9 were included. End-expiratory respiratory mechanics and end-expiratory CT-scan were obtained at baseline for each dog. Thereafter, dogs were ventilated with VT 15 ml kg−1 based on VTi and VTc, applied randomly. Respiratory mechanics and CT-scan were repeated at end-inspiration during VTi and VTc. Data analyzed with linear mixed models and reported as mean ± SD or median [range]. Statistical significance p < 0.05. The elastance of the lung, chest wall and respiratory system indexed by ideal body weight (IBW) were positively correlated with body fat percentage, whereas the functional residual capacity indexed by IBW was negatively correlated with body fat percentage. At end-expiration, aeration (%) was: hyperaeration 0.03 [0.00–3.35], normoaeration 69.7 [44.6–82.2], hypoaeration 29.3 [13.6–49.4] and nonaeration (1.06% [0.37–6.02]). Next to the diaphragm, normoaeration dropped to 12 ± 11% and hypoaeration increased to 90 ± 8%. No differences in aeration between groups were found at end-inspiration. Airway driving pressure (cm H2O) was higher (p = 0.002) during VTc (9.8 ± 0.7) compared with VTi (7.6 ± 0.4). Lung strain was higher (p = 0.014) during VTc (55 ± 21%) than VTi (38 ± 10%). The stress index was higher (p = 0.012) during VTc (SI = 1.07 [0.14]) compared with VTi (SI = 0.93 [0.18]). This study indicates that body fat percentage influences the magnitude of lung, chest wall, and total respiratory system elastance and resistance, as well as functional residual capacity. Further, these results indicate that obese dogs have extensive areas of hypoaerated lungs, especially in caudodorsal regions. Finally, lung strain and airway driving pressure, surrogates of lung deformation, are higher during VTc than during VTi, suggesting that in obese anesthetized dogs, ventilation protocols based on IBW may be advantageous.

Airway hyperresponsiveness induced by intermittent hypoxia in rats

This study investigated whether intermittent hypoxia (IH) induces airway hyperresponsiveness (AHR) and associated with lung inflammation. Male Brown Norway rats were exposed to 14-day IH or room air (RA) for 6 h/day. One day after the last exposure, total lung resistance to various doses of methacholine was measured as an index of bronchoconstrictive responses. Compared with RA controls, methacholine significantly induced an augmented bronchoconstriction in IH-exposed rats. Moreover, IH exposure evoked lung inflammation which was reflected by increased inflammatory cell infiltration, concentrations of interleukin-6 and prostaglandin E2 in bronchoalveolar lavage fluid, and lung lipid peroxidation. IH-induced AHR and lung inflammation were completely abolished by daily intraperitoneal injection of N-acetylcysteine (an antioxidant) or ibuprofen (a cyclooxygenase inhibitor), but not by apocynin (an inhibitor of NADPH oxidase) or vehicle. In conclusion, AHR and lung inflammation occur after 14-day IH exposure, with endogenous reactive oxygen species and cyclooxygenase metabolites being responsible for these responses.

Abstract P391: Inhalation Of Airborne Particulate Matter Alters Cardiovascular Function Of Alzheimer-prone Mice

Air pollution has detrimental effects on cardiovascular and lung function, and the extent of its pathological consequences continues to be uncovered. Recently, air pollution has been implicated in the development of Alzheimer Disease (AD) progression. AD and heart failure are common co-morbidities, giving reason to believe that cardiovascular dysfunction may contribute to AD. A known contributor to cardiovascular dysfunction-particulate matter (PM 2.5 , &lt; 2.5 μm diameter)—is a critical component of air pollution and is considered a risk factor for heart failure and AD development. This co-morbidity pattern and shared environmental risk factor prompted the hypothesis that PM 2.5 contributes to cardiovascular dysfunction in a transgenic mouse model of AD. We tested our hypothesis by subjecting 6-month-old transgenic (APP) and non-carrier wildtype (WT) male mice to filtered air (FA) or PM 2.5 for 5 days/week, 6 hours/day for 3 months (n = 34). Following exposure, echocardiography, pressure-volume (PV) loops, and respiratory mechanics were performed to detect cardiac and pulmonary changes associated with genotype and exposure conditions among the 3-month group. Echocardiography revealed left ventricular anterior wall thickness in systole was significantly elevated among PM-exposed APP mice compared to FA-exposed APP controls. PV data demonstrated significant reduced end-systolic elastance in PM-exposed mice compared to FA-exposed mice in both WT and APP mouse models, demonstrating impaired contractility. PV loops also showed that the time constant of isovolumetric relaxation was increased in PM-exposed compared to FA-exposed WT mice. APP mice experienced higher lung resistance and central airway resistance with an increasing dose of methacholine. Taken together, these findings indicate airborne particulate matter exposure causes cardiac and pulmonary dysfunction in a transgenic mouse model of AD.

Airway diameter at different transpulmonary pressures in ex vivo sheep lungs: implications for deep inspiration-induced bronchodilation and bronchoprotection

Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear. Understanding the mechanism will help us unravel the mystery of asthma pathophysiology. It has been postulated that straining airway smooth muscle (ASM) during a DI could lead to bronchodilation and bronchoprotection. The hypothesis is currently under debate, and a central question is whether ASM is sufficiently stretched during a DI for its contractility to be compromised. Besides bronchoconstriction, another contributor to lung resistance is airway heterogeneity. The present study examines changes in airway diameter and heterogeneity at different lung volumes. Freshly explanted sheep lungs were used in plethysmographic measurements of lung resistance and elastance at different lung volumes, whereas the airway dimensions were measured by computed tomography (CT). The change in airway diameter informed by CT measurements was applied to isolated airway ring preparations to determine the strain-induced loss of ASM contractility. We found that changing the transpulmonary pressure from 5 to 30 cmH2O led to a 51% increase in lung volume, accompanied by a 46% increase in the airway diameter with no change in airway heterogeneity. When comparable airway strains measured in the whole lung were applied to isolated airway rings in either relaxed or contracted state, a significant loss of ASM contractility was observed, suggesting that DI-induced bronchodilation and bronchoprotection can result from strain-induced loss of ASM contractility.

Effect of Theaflavin on Inflammatory and Remolding of Airway in the Asthma Mice

To study the effect of theaflavin on the airway’s inflammation and remodeling in mice with asthma. The mice were divided into the control, asthma model, and the theaflavin treatment groups to analyze the changes in pulmonary compliance and lung resistance of the mice with asthma to theaflavin treatment. The theaflavin treatment groups consisted of the low-dose (15 mg/kg theaflavin-intragastric administration), medium-dose (30 mg/kg), and high-dose (60 mg/kg) groups. Alveoli lavage liquid was gathered from the mice to count the number of inflammatory cells, and the levels of interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13), and eotaxin were detected by ELISA. The levels of proteins, such as transforming growth factor-1 (TGF-1), alpha-smooth muscle actin (α-SMA), CyclinD1,CyclinD2, Toll-like receptors-4 (TLR4), myeloid differentiation factor 88 (MyD88), and NF-κBp65, which showed the performance of lung tissue was tested by Western blotting. Compared to the control group, the lung resistance of the asthma model mice was increased, and compliance was decreased after increasing concentrations of acetylcholine (Mch) stimulation. Compared to the asthma model group, the pulmonary resistance was decreased, and pulmonar compliance was increased according to the rising concentration of Mch in theaflavin-L, theaflavin-M and theaflavin-H mice. Compared to the control group, the number of cells, macrophages, acidophilic cells, lymph, and neutrophile granulocytes increased in the alveolar perfusion fluid of asthmatic mice. The level of interleukin 4, interleukin 5, interleukin 13, and eotaxin, TGF-β1, α-SMA, Cyclin D1, MyD88, TLR4, Cyclin D2, and NF-κBp65 proteins of the lung was also increased. Compared to the model group, the number of cells, macrophages, acidophilic cells, lymph, and neutrophile granulocytes were decreased successively in the alveolar lavage fluid in the theaflavin-L, theaflavin-M, and theaflavin-H mice. Meanwhile, the content of interleukin 4, interleukin 5, interleukin 13, and eotaxin were decreased successively, and the level of TGF-β1, α-SMA, Cyclin D1, MyD88, TLR4, Cyclin D2, and NF-κBp65 protein increased successively in the theaflavin-L, theaflavin-M, and theaflavin-H mice. Theaflavin has been found to reduce airway inflammation, impede airway remodeling, and decrease the TLR 4/MyD88/NF-κB signaling in asthmatic mice.

Ginsenoside Rh1 attenuates ovalbumin-induced asthma by regulating Th1/Th2 cytokines balance.

Ginsenoside Rh1 (Rh1) has anti-inflammatory effects in asthma mice, but the underlying mechanism remains unclear. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to construct asthma model. Mice received Rh1 or tiotropium bromide 0.5 h before OVA challenge. Airway morphology and airway remodeling were assessed by HE staining and Masson's trichrome staining, respectively. Th1/Th2 cytokines in serum or broncho alveolar lavage fluid (BALF) were measured by ELISA kits. Rh1 significantly alleviated the lung resistance and airway resistance, and reduced the number of total inflammation cells, eosinophils, neutrophils, and lymphocytes in BALF of the asthmatic mice. The morphological changes and collagen deposition of airway were also reduced by Rh1 in asthmatic mice. The increase of Eotaxin, IL-4, IL-5, IL-13, and IL-33 and the decrease of IL-12 and IFN-γ in both BALF and serum of OVA exposed mice were reversed by Rh1. Rh1 attenuates OVA-induced asthma in the mice model by regulating Th1/Th2 cytokines balance.

Photodynamic Therapy in the Extracellular Matrix of Mouse Lungs: Preliminary Results of an Alternative Tissue Sterilization Process

Lung transplantation is one of the most difficult and delicate procedures among organ transplants. For the success of the procedure and survival of the new organ, the sterilization step for acellular lungs prior to recellularization is important to ensure that they are free of any risk of transmitting infections from the donor to the recipient subject. However, there are no available information concerning the lung mechanical parameters after sterilizing photodynamic therapy. The aim of this study was to evaluate the extracellular matrix (ECM) and lung mechanical parameters of decellularized lungs undergoing sterilizing photodynamic therapy (PDT). Besides, we also analyzed the lung after controlled infection with C. albicans in order to evaluate the effectiveness of PDT. The lung mechanical evaluation parameters, resistance ( R L ) and elastance ( E L ), exhibited no significant differences between groups. In addition, there were no PDT-induced changes in lung properties, with maintenance of the viscoelastic behavior of the lung scaffold after 1 h exposure to PDT. The ECM components remained virtually unchanged in the acellular lungs of both groups. We also showed that there was a reduction in fungal infection population after 45 minutes of PDT. However, more studies should be performed to establish and verify the effectiveness of PDT as a possible means for sterilizing lung scaffolds. This manuscript was presented as a master thesis of Nadua Apostólico at the postgraduate program in rehabilitation sciences, University Nove de Julho—UNINOVE.

Short‐term PM exposure and social defeat cause reduction in pulmonary and right ventricle function

Military members, first responders, and various other occupations are exposed to environments containing high levels of air pollution and psychological distress. While much is known about the effects of particulate matter (PM) and stress on cardiac and lung function, we investigated the interaction of these factors and whether the combination of prolonged PM and stress exposures exacerbate cardiac and lung function in a mouse model. Male C57Bl/6 mice were exposed to filtered air (FA) or PM at concentrations of 137.7 ± 70.76 (daily mean ± standard deviation) for five days/week for three weeks. A subset of each group was stressed by exposing them to a retired male aggressor for two hours/day, 3-5 nights/week (FA-stress and PM-stress groups). Echocardiography of the mice showed no changes in left ventricle (LV) systolic or diastolic indices, but a significant reduction in right ventricle (RV) stroke volume and cardiac output in the PM, FA-stress and PM-stress groups (P<0.05via two-way ANOVA) compared to FA. Pressure-volume loops found a reduction in contractility as the PM and PM-stress groups, but not FA-stress, had significantly reduced end-systolic elastance (Ees, P<0.05 via two-way ANOVA) compared to FA. Data on respiratory mechanics was acquired using the flexiVent FX2 (SCIREQ Inc.) system. With an increasing dose of methacholine, PM exposure caused an increase in lung resistance (Rrs), central airway resistance (Rn), and tissue damping (G) (area under the curve [AUC], P<0.05 via two-way ANOVA) compared to FA. The FA-stress and PM-stress groups had significantly increased lung elastance (Ers), Rrs, Rn, and G (AUC P<0.05 via two-way ANOVA) compared to FA. Tail-vein blood pressure measurements in these mice found that an increased diastolic, but not systolic pressure was induced by PM exposure, but not by stress (P<0.05via two-way ANOVA). Taken together, short-term exposure to PM with and without psychological distress impairs respiratory mechanics and RV function. These results suggest that even short-term exposure to PM, such as in occupational settings, causes notable dysfunction in cardiopulmonary function equal to stress.

Nebulized dexamethasone sodium phosphate in the treatment of horses with severe asthma.

BackgroundA study reported low systemic availability of injectable dexamethasone nebulized to healthy horses using the Flexineb mask. When used in horses with severe asthma and a different nebulizer, lack of efficacy and cortisol suppression were observed.HypothesisNebulized dexamethasone is as effective as PO administration for the treatment of severe asthma in horses.AnimalsTwelve horses with severe asthma from a research herd.MethodsRandomized clinical trial. Horses were divided into 2 groups and received 5 mg of dexamethasone sodium phosphate by nebulization using a Flexineb mask (NE, n = 6) or PO (OR, n = 6) q24h for 7 days. Lung function and serum cortisol concentrations were evaluated at baseline, after 4 days of treatment (D4) and 1 day after the last treatment (D8). Data were analyzed using linear mixed models with Benjamini‐Hochberg adjustments.ResultsLung resistance significantly improved at D4 (mean decrease ± SD, −1.5 ± 0.45 cm H₂O/L/s; 95% confidence interval [CI], −2; −0.6) and D8 (−1.4 ± 0.45 cm H₂O/L/s; 95% CI, −2.4; −0.5) compared to baseline in the OR group only (P = .004 and .01, respectively). Serum cortisol concentration was significantly decreased at D4 and D8 for both groups (maximum decrease, −1.2 ± 0.3 μg/dL; 95% CI, −1.9; −0.6 at D4 for NE group and −2.2 ± 0.3 μg/dL; 95% CI, −2.8; −1.6 at D8 for OR group; P < .001).Conclusions and Clinical ImportanceOral, but not nebulized dexamethasone is an effective therapy for horses with severe asthma and both treatment modalities inhibit the hypothalamic‐pituitary‐adrenal axis.

Development of Oral Chewable Tablets Containing Montelukast Nanoparticles for the Treatment of Childhood Asthma: Preclinical Study in Animal Model

The aim of the present study was to formulate oral chewable tablets of Montelukast (MTL) in the form of nanoparticles (NP’s). The MTL loaded NP’s were formulated by ionotropic external gelation method using tripolyphosphate (TPP) as crosslinking agent and Tween 60 as surfactant. NP’s were characterized for drug loading, encapsulation efficiency, surface morphology, saturation solubility, particle size, zeta potential and polydispersity index. The optimized NP formulation was used for development of chewable tablets using direct compression method. The prepared tablets were characterized for disintegration test, dissolution, thickness, hardness, friability and assay. The optimized formulation was evaluated in asthamatic animals to demonstrate the efficiency in asthama. The encapsulation efficiency of NP’s was found between 91.24 to 98.21% while drug loading was in the range of 10.09–14.25%. All formulations were found of nanosized in nature (110 to 200 nm) with excellent zeta potential (20.12 to 22.27 mV). PDI of all NP formulations were found within acceptable limit (less than 0.3). The nanoparticles were found spherical in shape with smooth surface. The saturation solubility of MTL was enhanced nearly 10 times (92 mg/ml) as compared to pure MTL saturation solubility. All physical parameters of the tablets were found within range. The optimized tablets showed disintegration time of 20 sec while other formulations showed DT in the rage of 35–57 sec. Tab1 (Optimized formulation) showed almost 100% MTL release from chewable tablets within the period of 30 min. Reduction in lung resistance (RI) was found in animals treated with Tab1. This reduction in RI was found nearly two fold and three fold as compare to MTL treated and control group animals. These observations clearly support the efficacy of chewable tablets containing nanoparticulate MTL in asthmatic animals.

GLUT1 Expression in Tumor-Associated Neutrophils Promotes Lung Cancer Growth and Resistance to Radiotherapy.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils. SIGNIFICANCE: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2345/F1.large.jpg.

Long-term outcomes of percutaneous closure of patent ductus arteriosus associated with unilateral absence of a pulmonary artery.

This study aimed to evaluate the long-term outcomes of patients with patent ductus arteriosus (PDA) associated with unilateral absence of a pulmonary artery (UAPA). Patients diagnosed with PDA associated with UAPA between January 2005 and June 2019 were retrospectively enrolled in this study. Demographic and clinical characteristics, treatments, and follow-up information were evaluated. A total of 11 patients were diagnosed with PDA associated with UAPA. Percutaneous closure was successfully conducted in nine patients. The mean diameters of the PDA measured by aortogram and occluders were 5.3 ± 1.8 mm and 11.5 ± 3.9 mm, respectively. The median pulmonary systemic flow ratio (Qp:Qs) in five patients was 1.41, and the median total lung resistance was 12 Wood Units. The mean systolic pulmonary artery (PA) pressure was 68.3 ± 19.1 mmHg. In five patients with pre- and postprocedure catheter data, the systolic pulmonary arterial pressure decreased significantly after closure (from 77.0 ± 20.2 to 58.8 ± 17.5 mmHg; p = .024), as did the mean pulmonary arterial pressure (from 58.2 ± 14.6 to 39.0 ± 14.1 mmHg; p = .18). The PA pressure and heart size gradually decreased to normal levels in eight patients, and their quality of life was significantly improved. The ratio of lung to systemic circulation pressure was less than 0.75. In appropriate patients with PDA associated with UAPA, transcatheter closure of PDA has the potential to improve PA hypertension. A ratio of lung to systemic circulation pressure less than 0.75 may be an important reference index for predicting whether PA pressure can be reduced to a normal level after occlusion.

Developmental Insights into Lung Cancer

Lung cancer continues to be the number one cancer killer. Despite a surge of therapeutic advances in recent years, lung cancer remains fatal when it presents at a stage too advanced for surgical resection. In part, this is due to the disappointing reality of inevitable drug resistance in the face of highly effective, mutation-specific chemotherapy and the limited efficacy of immune checkpoint blockade. Yet, with the increasing application and integration of diverse genomic profiling approaches and the advent of high-content single-cell technologies, the mechanisms of lung cancer initiation, evolution, spread, and resistance are being unraveled at unprecedented resolution. Increasingly sophisticated mouse genetic, xenotransplantation, and ex vivo assays are also enabling functional validation and empiric screening of new therapeutic candidates. In this review, I highlight recent insights into the genetic, cellular, and molecular mechanisms of lung cancer and relate them to the normal biology of the developing and mature lung.