Lung Resistance Research Articles

Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model.

Asthma and allergies are complex, chronic inflammatory diseases in which genetic and environmental factors are crucial. Protection against asthma and allergy development in the context of farming environment is established by early animal contact, unpasteurized milk consumption and gut microbiota maturation. The human β-defensin 2 (hBD-2) is a host defense peptide present almost exclusively in epithelial tissues, with pronounced immunomodulatory properties, which has recently been shown to ameliorate asthma and IBD in animal models. We hypothesized that adequate hBD-2 secretion plays a role in the protection against asthma and allergy development and that genetic variations in the complex gene locus coding for hBD-2 may be a risk factor for developing these diseases, if as a consequence, hBD-2 is insufficiently produced. We used MALDI-TOF MS genotyping, sequencing and a RFLP assay to study the genetic variation including mutations, polymorphisms and copy number variations in the locus harboring both genes coding for hBD-2 (DEFB4A and DEFB4B). We administered hBD-2 orally in a mouse model of house dust mite (HDM)-asthma before allergy challenge to explore its prophylactic potential, thereby mimicking a protective farm effect. Despite the high complexity of the region harboring DEFB4A and DEFB4B we identified numerous genetic variants to be associated with asthma and allergy in the GABRIELA Ulm population of 1,238 children living in rural areas, including rare mutations, polymorphisms and a lack of the DEFB4A. Furthermore, we found that prophylactic oral administration of hBD-2 significantly curbed lung resistance and pulmonary inflammation in our HDM mouse model. These data indicate that inadequate genetic capacity for hBD-2 is associated with increased asthma and allergy risk while adequate and early hBD-2 administration (in a mouse model) prevents atopic asthma. This suggests that hBD-2 could be involved in the protective farm effect and may be an excellent candidate to confer protection against asthma development.

α1-Antitrypsin alleviates inflammation and oxidative stress by suppressing autophagy in asthma

BackgroundAsthma is considered an incurable disease, although many advances have been made in asthma treatments in recent years. Therefore, elucidating the pathological mechanisms and seeking novel and effective therapeutic strategies for asthma are urgently needed. MethodsAirway resistance was measured by whole-body plethysmography. H&E staining was used to observe the morphological changes in the lung. Oxidative stress was assessed by measuring the levels of MDA, CAT and SOD. Gene expression was analysed by western blotting and RT-qPCR. ELISA was used to analyse the concentrations of IL-4, IL-5 and IFN-γ. ResultsIn the present study, we successfully established in vivo and in vitro asthma models. OVA administration led to elevated lung resistance, cell counts in BALF, and cytokine secretion, impaired airway structure and enhanced oxidative stress and autophagy in a mouse model of asthma, while IL-13 induced inflammation, oxidative stress and autophagy in BEAS-2B cells. A1AT reduced lung resistance and cell counts in BALF and suppressed inflammation, oxidative stress and autophagy in a mouse model of asthma and IL-13-induced BEAS-2B cells. Mechanistic investigations revealed that autophagy activation compromised the protective effect of A1AT on IL-13-induced BEAS-2B cells. Further mechanistic studies revealed that A1AT alleviated inflammation and oxidative stress by inhibiting autophagy in the context of asthma. ConclusionWe demonstrated that A1AT could alleviate inflammation and oxidative stress by suppressing autophagy in the context of asthma and thus ameliorate asthma. Our study revealed novel pathological mechanisms and provided novel potential therapeutic targets for asthma treatment.

LncRNA APCDD1L-AS1 induces icotinib resistance by inhibition of EGFR autophagic degradation via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis in lung adenocarcinoma

BackgroundEpidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance is the major obstacle in the treatment of lung adenocarcinoma (LUAD) patients harboring EGFR-sensitive mutations. However, the long non-coding RNAs (lncRNAs) related to EGFR-TKIs resistance and their functional mechanisms are still largely unknown. This study aimed to investigate the role and regulatory mechanism of lncRNA APCDD1L-AS1 in icotinib resistance of lung cancer.MethodsMolecular approaches including qRT-PCR, MTT assay, colony formation, RNA interference and cell transfection, RNA immunoprecipitation (RIP), dual luciferase reporter assay, RNA fluorescence in situ hybridization, TUNEL assay, flow cytometry, immunoblotting, xenograft model and transcriptome sequencing were used to investigate the mechanism of APCDD1L-AS1 in icotinib resistance.ResultsA novel lncRNA, APCDD1L-AS1 was identified as the most significantly upregulated lncRNA in icotinib-resistant LUAD cells by the transcriptome sequencing and differential lncRNA expression analysis. We found that APCDD1L-AS1 not only promoted icotinib resistance, but also upregulated the protein expression level of EGFR. Mechanistically, APCDD1L-AS1 promoted icotinib resistance and EGFR upregulation by sponging with miR-1322/miR-1972/miR-324-3p to remove the transcription inhibition of SIRT5. Furthermore, SIRT5 elevated EGFR expression and activation by inhibiting the autophagic degradation of EGFR, finally promoting icotinib resistance. Consistently, the autophagy initiator rapamycin could decrease EGFR levels and increase the sensitivity of icotinib-resistant LUAD cells to icotinib.ConclusionAPCDD1L-AS1 could promote icotinib resistance by inhibiting autophagic degradation of EGFR via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis. The combination of autophagy initiator and EGFR-TKIs might serve as a potential new strategy for overcoming EGFR-TKIs resistance in LUAD patients.

Immunoexpression and Prognostic Significance of Multidrug Resistance Markers in Feline Mammary Carcinomas

Feline mammary carcinomas (FMCs) are commonly characterized by high clinical aggressiveness and poor prognosis. FMCs share many features with the corresponding human disease, allowing the comparative investigation of tumour biology and therapeutic strategies, including multidrug resistance (MDR) mechanisms. Although transporting/binding proteins, including permeability glycoprotein (P-gp), lung resistance protein (LRP) and metallothionein (MT), are frequently associated with tumour aggressiveness and unresponsiveness to chemotherapy in human breast cancer, they have not been analysed in FMCs. We investigated the immunoexpression of P-gp, LRP and MT in FMCs and their correlation with clinicopathological parameters and overall survival (OS) time in 46 FMCs, with a median follow-up period of 289 days. These markers were co-expressed in 85% of tumours. P-gp was expressed in 93.4% of FMCs and was positively associated with tumour grade (P=0.049). While unequivocally observed in all FMCs, LRP immunoexpression did not correlate with any clinicopathological parameters or OS. Expression of MT was significant in triple-negative basal- and normal-like molecular subtypes of FMCs (P=0.023). The concurrent expression of MDR proteins indicates the potential existence of chemotherapy resistance-related mechanisms in FMCs. The positive association between P-gp and MT immunoexpression and aggressive phenotypes could open new therapeutic and translational strategies for FMCs.

Carboxypeptidase inhibition by NvCI suppresses airway hyperreactivity in a mouse asthma model

Carboxypeptidase inhibition by NvCI suppresses airway hyperreactivity in a mouse asthma model

Simultaneous ventilation in the Covid-19 pandemic. A bench study

COVID-19 pandemic sets the healthcare system to a shortage of ventilators. We aimed at assessing tidal volume (VT) delivery and air recirculation during expiration when one ventilator is divided into 2 test-lungs. The study was performed in a research laboratory in a medical ICU of a University hospital. An ICU (V500) and a lower-level ventilator (Elisée 350) were attached to two test-lungs (QuickLung) through a dedicated flow-splitter. A 50 mL/cmH2O Compliance (C) and 5 cmH2O/L/s Resistance (R) were set in both A and B test-lungs (A C50R5 / B C50R5, step1), A C50-R20 / B C20-R20 (step 2), A C20-R20 / B C10-R20 (step 3), and A C50-R20 / B C20-R5 (step 4). Each ventilator was set in volume and pressure control mode to deliver 800mL VT. We assessed VT from a pneumotachograph placed immediately before each lung, pendelluft air, and expiratory resistance (circuit and valve). Values are median (1st-3rd quartiles) and compared between ventilators by non-parametric tests. Between Elisée 350 and V500 in volume control VT in A/B test- lungs were 381/387 vs. 412/433 mL in step 1, 501/270 vs. 492/370 mL in step 2, 509/237 vs. 496/332 mL in step 3, and 496/281 vs. 480/329 mL in step 4. In pressure control the corresponding values were 373/336 vs. 430/414 mL, 416/185 vs. 322/234 mL, 193/108 vs. 176/ 92 mL and 422/201 vs. 481/329mL, respectively (P<0.001 between ventilators at each step for each volume). Pendelluft air volume ranged between 0.7 to 37.8 ml and negatively correlated with expiratory resistance in steps 2 and 3. The lower-level ventilator performed closely to the ICU ventilator. In the clinical setting, these findings suggest that, due to dependence of VT to C, pressure control should be preferred to maintain adequate VT at least in one patient when C and/or R changes abruptly and monitoring of VT should be done carefully. Increasing expiratory resistance should reduce pendelluft volume.

Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

Older Age of Fontan Completion is Associated With Impaired Lung Function

Fontan patients have reduced lung volumes and abnormal gas transfer. The mechanisms for this are poorly understood. We aimed to examine the association between: i) alveolar volume (VA), capillary blood volume (VC) and alveolar capillary membrane function (DmCO) and diffusion capacity of carbon monoxide (DLCO); ii) these parameters and lung resistance (R5) and elastance (X5); and iii) clinical parameters and lung function.

Caveolin-1 promotes radioresistance via IRGM-regulated autophagy in lung cancer.

BackgroundRadiotherapy is the standard therapeutic approach for non-small cell lung cancers (NSCLCs). However, radiotherapy resistance accounts for major treatment failures in NSCLC patients. Recently, targeting autophagy-related signaling has shown potential to improve radiotherapy. Furthermore, some studies have reported that caveolin-1 (Cav1), a primary scaffolding protein of caveolae, is positively associated with NSCLC progression and cell autophagy. However, the function of Cav1-mediated autophagy in NSCLC radioresistance remains largely unknown.MethodsThe NSCLC irradiation (IR)-resistant cell lines H358-IRR and A549-IRR were used for in vitro analysis. Real-time quantitative PCR (qPCR), western blot, cell counting kit-8 (CCK-8), colony formation and transmission electron microscopy analyses were performed to explore the relationship between Cav1 and immunity-related GTPase family M protein (IRGM)-regulated autophagy in the radiation resistance of lung cancers.ResultsCav1 was significantly overexpressed in H358-IRR and A549-IRR cells compared to their parental counterparts. Knockdown of Cav1 significantly decreased the proliferation of IR-resistant NSCLC cells. Combinational treatment of IR and siRNA of Cav1 showed enhanced inhibition of the cell viability and colony formation of IR-resistant NSCLC cells. In addition, Cav1 overexpression could upregulate the autophagic proteins microtubule associated protein 1 light chain 3 II (LC3 II), Beclin-1 and Sequestosome 1 (SQSTM1/p62) in parental NSCLC cells, while Cav1 downregulation by siRNA inhibited the expression of LC3 II, Beclin-1 and p62 and the formation of autophagosomes in IR-resistant NSCLC cells. Furthermore, we observed that IRGM was downregulated after knockdown of Cav1 in IR-resistant NSCLC cells. Thus, Cav1 was observed to promote autophagy and increase IR-resistant cell survival by targeting IRGM.ConclusionsThe results of our study showed that Cav1 is involved in the development of IR resistance in NSCLC through IRGM-regulated autophagy and can be considered as a potential therapeutic target for improving the radiosensitivity of NSCLC.

Elevated expression of miR-146 involved in regulating mice pulmonary dysfunction after exposure to PM2.5.

Exposure to atmospheric fine particulate matter has short-term and long-term adverse effects on pulmonary function, especially PM2.5; however, early lung function impairment is not easily detected in time. Notably, microRNAs (miRNAs) have been classified as novel biomarkers for diseases related to PM. Thus, the purpose of this study was to investigate whether miR-146 was related to the decline of lung function after exposure to air pollution. Thirty BALB/c mice were subjected to different concentrations of PM2.5 by noninvasive tracheal instillation for 56 days (two times one week), after which we detected the histopathological changes of mice lung, pulmonary functions, pro-inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue homogenate, and the relative expression of microRNA-146a and -146b. When BALB/c mice were exposed to 10 mg/kg PM2.5, severe changes such as widened alveolar interval and diffuse infiltration of macrophages with engulfed PM2.5 particles (dust cells) were found. Peak inspiratory flow (PIF) and peak expiratory flow (PEF) were decreased significantly. Expiratory resistance (Re) and inspiratory resistance (Ri) were increased significantly in the 5 mg/kg and 10 mg/kg PM2.5 groups, meanwhile lung resistance increased and MVV (maximum minute ventilation) decreased from the general tendency; however, pro-inflammatory factors interleukin-6 (IL-6), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were increased dramatically. MiR-146a and miR-146b were elevated remarkably in the PM2.5 groups compared to the NS group. We also found miR-146 had negative relationships with PIF and PEF, especially miR-146b. Thus, elevated miR-146a and miR-146b may have a relationship with pulmonary dysfunction after PM2.5 chronic exposure.

Frequency and Clinical Significance of the Expression of the Multidrug Resistance Proteins MDR1/P-Glycoprotein, MRP1, and LRP in Acute Myeloid Leukemia. A Southwest Oncology Group Study

Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease.

Lrp1 Regulation of Pulmonary Function. Follow-Up of Human GWAS in Mice.

Human genome-wide association studies (GWASs) have identified more than 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. SNPs in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWASs. Using murine models, we investigated the effect of genetic disruption of the Lrp1 gene in smooth muscle cells on pulmonary function in naive animals and after exposure to bacterial LPS or house dust mite extract. Disruption of Lrp1 in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Furthermore, disruption of Lrp1 in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in BAL fluid were increased in animals with Lrp1 disruption. The difference in airway responsiveness by genotype observed in naive animals was not observed after LPS or house dust mite extract exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with Lrp1 disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish LRP1 as the causal gene at this GWAS locus.

Functional Doxorubicin-Loaded Omega-3 Unsaturated Fatty Acids Nanoparticles in Reversing Hepatocellular Carcinoma Multidrug Resistance.

BackgroundThis study investigated a nanoparticle drug delivery system to reverse multidrug resistance (MDR) and assessed its anticancer efficacy in hepatocellular carcinoma (HCC).Material/MethodsDocosahexaenoic acid (DHA) was used as the functional excipient and doxorubicin (DOX) as the chemotherapeutic drug to synthesize DOX nanoparticles (DOX-nano). The human HCC cell line HepG2 was used for experiments. HepG2/DOX, HepG2+DOX, HepG2+DOX-nano, HepG2/DOX+DOX, and HepG2/DOX+DOX-nano groups cells were treated with DOX or DOX-nano (5 μg/mL). Nude mice bearing a HepG2/DOX xenograft were divided into model, DOX, vector-nano, and DOX-nano groups and injected with saline, DOX reagent, vector-nano, and DOX-nano (2 mg/kg), respectively. Next, cytotoxicity, cellular uptake, cell apoptosis and migration, fluorescence imaging, TUNEL assay, and tumor inhibition effects were assessed in vitro and in vivo. Furthermore, expression of MDR-related proteins was also detected using western blotting.ResultsFluorescence imaging showed that the DOX uptake in the DOX-nano-treated group was the strongest in the HCC cells or tumors. Cell apoptosis was significantly increased in DOX-nano-treated HepG2/DOX cells and tumors, and cell migration was significantly inhibited in the DOX-nano-treated HepG2/DOX cells compared with the other groups. The tumor inhibitory rate in DOX-nano-injected tumors was also significantly higher than in other groups. The expression of breast cancer resistance protein, B-cell lymphoma 2, lung resistance protein, multidrug resistance protein, and protein kinase C alpha was significantly decreased in DOX-nano-treated HepG2/DOX cells and xenograft tumors. Significantly better antitumor and MDR-reversing effects were also observed in the HepG2+DOX group compared with the HepG2/DOX group.ConclusionsThis study revealed the potential efficacy of a DOX-nano drug delivery system for the treatment of HCC, using HepG2/DOX cells and nude mice bearing HepG2/DOX xenografts.

Response of Very Premature Infants with Bronchopulmonary Dysplasia to Inhaled Salbutamol

Bronchopulmonary Dysplasia (BPD) is the most common chronic respiratory disease found in premature infants following prolonged supplemental oxygen and mechanical ventilation. Although salbutamol, a selective ß2 agonist, is known to relax the hypertrophied smooth muscles around the small airways in adults, earlier literature has suggested that neonates did not have enough peribronchial smooth muscle for constriction and thus lacked a bronchodilatory response to ß2 agonists. The present study was designed to determine whether infants of less than 32 weeks gestational age with elevated lung resistance were responsive to salbutamol. Nineteen premature infants (mean gestational age 26.0 +/- 2.1 weeks and mean birth weight 851.3 +/- 244.4 g) were recruited for the study. Immediately before and 30 minutes after the commencement of nebulized salbutamol administration, a minimum of 15 breaths were measured and analyzed for each patient. From this breath-by-breath analysis, the lung mechanics and Work of Breathing (WOB) were calculated. Results were then compared by paired t-tests. The use of salbutamol resulted in a significant improvement in airway resistance (p = 0.008) and tendency for impedance reduction. These results indicate that very premature infants (&lt; 32 weeks) with BPD respond favorably to bronchodilators. Although the mechanism of action remains to be elucidated, salbutamol most probably achieves its effects through the relaxation of the hypertrophied peribronchial smooth muscle. Early intervention to relieve airway obstruction may promote early weaning from mechanical ventilation and diminish both duration and severity of BPD.

Maternal high-fat diet in mice alters immune regulation and lung function in the offspring.

PUFA modulate immune function and have been associated with the risk of childhood atopy and asthma. We investigated the effect of maternal fat intake in mice on PUFA status, elongase and desaturase gene expression, inflammatory markers and lung function in the offspring. C57BL/6J mice (n 32) were fed either standard chow (C, 20·4 % energy as fat) or a high-fat diet (HFD, 39·9 % energy as fat) for 4 weeks prior to conception and during gestation and lactation. At 21 d of age, offspring were weaned onto either the HFD or C, generating four experimental groups: C/C, C/HF, HF/C and HF/HF. Plasma and liver fatty acid composition were measured by GC and gene expression by quantitative PCR. Lung resistance to methacholine was assessed. Arachidonic acid concentrations in offspring plasma and liver phospholipids were increased by HFD; this effect was greater in the post-natal HFD group. DHA concentration in offspring liver phospholipids was increased in response to HFD and was higher in the post-natal HFD group. Post-natal HFD increased hepatic fatty acid desaturase (FADS) 2 and elongation of very long-chain fatty acid 5 expression in male offspring, whereas maternal HFD elevated expression of FADS1 and FADS2 in female offspring compared with males. Post-natal HFD increased expression of IL-6 and C-C motif chemokine ligand 2 (CCL2) in perivascular adipose tissue. The HFD lowered lung resistance to methacholine. Excessive maternal fat intake during development modifies hepatic PUFA status in offspring through regulation of gene expression of enzymes that are involved in PUFA biosynthesis and modifies the development of the offspring lungs leading to respiratory dysfunction.

Lung function is associated with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) levels in school-aged children

BackgroundTumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. A complex relationship exists between TRAIL and the lung where both elevated TRAIL and TRAIL deficiency are associated with lung impairment. In neonatal mice, TRAIL is thought to translate respiratory infections into chronic lung disease but the association between TRAIL and lung function in childhood has not been assessed. AimTo assess the cross-sectional relationship between TRAIL levels and lung function in school-aged children. MethodsThe study cohort consisted of 170 school-aged children attending four schools in Malmö, Sweden. Lung volumes, impulse oscillometry (IOS) and serum TRAIL were measured for all children. Linear regression was used to assess changes in lung function per 1-SD increase in TRAIL. General linear models were used to assess mean lung function by tertiles (T) of TRAIL. ResultsMean age was 9.9 years (±0.6). A 1-SD increase in TRAIL was associated with lower values of FEV1 and FEV1/VC (change in FEV1 (L) and FEV1/VC ratio: −0.047, p-value 0.002, and −0.011, p-value 0.020, respectively) and higher values of lung resistance (change in R5 and R20 (kPa/(L/s)): 0.035, p-value <0.001 and 0.027, p-value 0.004, respectively). These associations remained significant after excluding children with pre-existing lung disease. Higher TRAIL levels were associated with more negative values for X5 in general linear models (Mean X5 (kPa/(L/s)) in T1 (low TRAIL): −0.193 vs T3 (high TRAIL): −0.216, p-value 0.026). ConclusionsHigh TRAIL levels are significantly associated with markers of pulmonary airflow obstruction in school-aged children.

Experimental investigation of right‐left flow balance concepts for a total artificial heart

A total artificial heart (TAH) must be designed to autonomously balance the flows of the systemic and pulmonary circulation to prevent potentially lethal lung damage. The flow difference between the systemic and pulmonary circulation is mainly caused by the bronchial (arteries) shunt flow and can change dynamically. The ReinHeart TAH consists of only one actuator that ejects blood alternately from the right and left pump chamber. This design entails a coupling of the right and left stroke and thus, complicates the independent adaptation of the right and left flow. In this experimental study on the ReinHeart TAH, four concepts to keep the flows well balanced were investigated using an active mock circulation loop for data acquisition. Three concepts are based on mechanical design changes (variation of pusher plate shape, flexible right pump chamber housing, and reduced right stroke volume) to achieve a static flow difference. In combination with these static concepts, a concept influencing the ratio of systole and diastole duration to respond to dynamic changes was studied. In total, four measurement series, each with 270 operating points, to investigate the influence of circulatory filling volume, heart rate, bronchial shunt flow, and lung resistance were recorded. In the course of this study, we introduce a concept deviation indicator, providing information about the efficiency of the concepts to balance the flows based on changes in lung's blood pressures. Furthermore, the distribution of the measured data was evaluated based on bubble plot visualizations. The investigated variation of the right pusher plate shape results in high lung pressures which will cause lethal lung damage. In comparison, a flexible right pump chamber housing shows lower lung pressures, but it still has the potential to damage the lungs. Reducing the stroke volume of the right pump chamber results in proper lung pressures. The flow balance can dynamically be influenced with a positive effect on the lung pressures by choosing a suitable systole-diastole-ratio. The results of this study suggest that an adequate right-left flow balance can be achieved by combining the mechanical concept of a reduced right stroke volume with an active control of the systole-diastole-ratio.

Inactivation of AKT/NF‑κB signaling by eurycomalactone decreases human NSCLC cell viability and improves the chemosensitivity to cisplatin.

The high activation of protein kinase B (AKT)/nuclear factor-κB (NF-κB) signaling has often been associated with the induction of non-small cell lung cancer (NSCLC) cell survival and resistance to cisplatin, which is one of the most widely used chemotherapeutic drugs in the treatment of NSCLC. The inhibition of AKT/NF-κB can potentially be used as a molecular target for cancer therapy. Eurycomalactone (ECL), a quassinoid from Eurycoma longifolia Jack, has previously been revealed to exhibit strong cytotoxic activity against the human NSCLC A549 cell line, and can inhibit NF-κB activity in TNF-α-activated 293 cells stably transfected with an NF-κB luciferase reporter. The present study was the first to investigate whether ECL inhibits the activation of AKT/NF-κB signaling, induces apoptosis and enhances chemosensitivity to cisplatin in human NSCLC cells. The anticancer activity of ECL was evaluated in two NSCLC cell lines, A549 and Calu-1. ECL decreased the viability and colony formation ability of both cell lines by inducing cell cycle arrest and apoptosis through the activation of pro-apoptotic caspase-3 and poly (ADP-ribose) polymerase, as well as the reduction of anti-apoptotic proteins Bcl-xL and survivin. In addition, ECL treatment suppressed the levels of AKT (phospho Ser473) and NF-κB (phospho Ser536). Notably, ECL significantly enhanced cisplatin sensitivity in both assessed NSCLC cell lines. The combination treatment of cisplatin and ECL promoted cell apoptosis more effectively than cisplatin alone, as revealed by the increased cleaved caspase-3, but decreased Bcl-xL and survivin levels. Exposure to cisplatin alone induced the levels of phosphorylated-AKT and phosphorylated-NF-κB, whereas co-treatment with ECL inhibited the cisplatin-induced phosphorylation of AKT and NF-κB, leading to an increased sensitization effect on cisplatin-induced apoptosis. In conclusion, ECL exhibited an anticancer effect and sensitized NSCLC cells to cisplatin through the inactivation of AKT/NF-κB signaling. This finding provides a rationale for the combined use of chemotherapy drugs with ECL to improve their efficacy in NSCLC treatment.

PEEP/ FIO2 ARDSNet Scale Grouping of a Single Ventilator for Two Patients: Modeling Tidal Volume Response.

The COVID-19 pandemic is creating ventilator shortages in many countries that is sparking a conversation about placing multiple patients on a single ventilator. However, on March 26, 2020, six leading medical organizations released a joint statement warning clinicians that attempting this technique could lead to poor outcomes and high mortality. Nevertheless, hospitals around the United States and abroad are considering this technique out of desperation (eg, New York), but there is little data to guide their approach. The overall objective of this study is to utilize a computational model of mechanically ventilated lungs to assess how patient-specific lung mechanics and ventilator settings impact lung tidal volume (VT). We developed a lumped-parameter computational model of multiple patients connected to a shared ventilator and validated it against a similar experimental study. We used this model to evaluate how patient-specific lung compliance and resistance would impact VT under 4 ventilator settings of pressure control level, PEEP, breathing frequency, and inspiratory:expiratory ratio. Our computational model predicts VT within 10% of experimental measurements. Using this model to perform a parametric study, we provide proof-of-concept for an algorithm to better match patients in different hypothetical scenarios of a single ventilator shared by > 1 patient. Assigning patients to preset ventilators based on their required level of support on the lower PEEP/higher [Formula: see text] scale of the National Institute of Health's National Heart, Lung, and Blood Institute ARDS Clinical Network (ARDSNet), secondary to lung mechanics, could be used to overcome some of the legitimate concerns of placing multiple patients on a single ventilator. We emphasize that our results are currently based on a computational model that has not been validated against any preclinical or clinical data. Therefore, clinicians considering this approach should not look to our study as an exact estimate of predicted patient VT values.

Bulleyaconitine A inhibits the lung inflammation and airway remodeling through restoring Th1/Th2 balance in asthmatic model mice.

The current study aimed to study the effects of Bulleyaconitine A (BLA) on asthma. Asthmatic mice model was established by ovalbumin (OVA) stimulation, and the model mice were treated by BLA. After BLA treatment, the changes in lung and airway resistances, total and differential leukocytes in the bronchoalveolar lavage fluid (BALF) were detected, and the changes in lung inflammation and airway remodeling were observed. Moreover, the secretion of IgE, Th1/Th2-type and IL-17A cytokines in BALF and serum of the asthmatic mice were determined. The resuts showed that BLA attenuated OVA-induced lung and airway resistances, inhibited the inflammatory cell recruitment in BALF and the inflammation and airway remodeling of the asthmatic mice. In addition, BLA suppressed the secretion of IgE, Th2-type cytokines, and IL-17A, but enhanced secretions of Th1-type cytokines in BALF and serum. The current study discovered that BLA inhibited the lung inflammation and airway remodeling via restoring the Th1/Th2 balance in asthmatic mice.