Adult Lung Research Articles

Decellularized Spinach Biomaterials Support Physiologically Relevant Mechanical Cyclic Strain and Prompt a Stretch-Induced Cellular Response.

Recently, decellularized plant biomaterials have been explored for their use as tissue engineered substitutes. Herein, we expanded upon the investigation of the mechanical properties of these materials to explore their elasticity as many anatomical areas of the body require biomechanical dynamism. We first constructed a device to secure the scaffold and induce a strain within the physiological range of the normal human adult lung during breathing (12-20 movements/min; 10-20% elongation). Results showed that decellularized spinach leaves can support cyclic strain for 24 h and displayed heterogeneous local strain values (7.76-15.88%) as well as a Poisson's ratio (0.12) similar to that of mammalian lungs (10.67-19.67%; 0.01), as opposed to an incompressible homogeneous standard polymer (such as PDMS (10.85-12.71%; 0.4)). Imaging and mechanical testing showed that the vegetal scaffold exhibited strain hardening but maintained its structural architecture and water retention capacity, suggesting an unaltered porosity. Interestingly, we also showed that cells seeded on the scaffold can also sense the mechanical strain as demonstrated by a nuclear reorientation perpendicular to strain direction (63.3° compared to 41.2° for nonstretched cells), a nuclear location of YAP and increased expression of YAP target genes, a high cytoplasmic calcium level, and an elevated expression level of collagen genes (COL1A1, COL3A1, COL4A1, and COL6A) with an increased collagen secretion at the protein level. Taken together, these data demonstrated that decellularized plant leaf tissues have an inherent elastic property similar to that found in the mammalian system to which cells can sense and respond.

Differential effects of age, sex and dexamethasone therapy on ACE2/TMPRSS2 expression and susceptibility to SARS-CoV-2 infection.

ACE2 and TMPRSS2 are crucial for SARS-CoV-2 entry into the cell. Although ACE2 facilitates viral entry, its loss leads to promoting the devastating clinical symptoms of COVID-19 disease. Thus, enhanced ACE2/TMPRSS2 expression is likely to increase predisposition of target cells to SARS-CoV-2 infection. However, little evidence existed about the biological kinetics of these two enzymes and whether dexamethasone treatment modulates their expression. Here, we show that the expression of ACE2 at the protein and mRNA levels was significantly higher in the lung and heart tissues of neonatal compared to adult mice. However, the expression of TMPRSS2 was developmentally regulated. Our results may introduce a novel concept for the reduced susceptibility of the young to SARS-CoV-2 infection. Moreover, ACE2 expression but not TMPRSS2 was upregulated in adult female lungs compared to their male counterparts. Interestingly, the ACE2 and TMPRSS2 expressions were upregulated by dexamethasone treatment in the lung and heart tissues in both neonatal and adult mice. Furthermore, our findings provide a novel mechanism for the observed differential therapeutic effects of dexamethasone in COVID-19 patients. As such, dexamethasone exhibits different therapeutic effects depending on the disease stage. This was supported by increased ACE2/TMPRSS2 expression and subsequently enhanced infection of normal human bronchial epithelial cells (NHBE) and Vero E6 cells with SARS-CoV-2 once pre-treated with dexamethasone. Therefore, our results suggest that individuals who take dexamethasone for other clinical conditions may become more prone to SARS-CoV-2 infection.

Survival Outcomes of Lung Transplant Recipients From Donors With Abnormal Kidney Function

BackgroundRecovering lungs with pulmonary edema due to abnormal kidney function is considered one of the expanded selection criteria for lung transplant. The aim of this study is to assess lung transplant recipients’ survival from donors with abnormal kidney function and to determine differences in lung recovery rates from donors with and donors without abnormal kidney function. MethodsWe reviewed the United Network for Organ Sharing registry for first-time adult lung transplant donors and recipients from June 2005 to March 2017. Donor kidney function was categorized into three groups based on estimated glomerular filtration rate: group I, greater than 60 mL/min; group II, 15 to 59 mL/min; and group III, less than 15 mL/min. Recipient survival was stratified based on estimated glomerular filtration rate using Kaplan-Meier. A multivariate Cox Regression model with known risk factors that affect survival was used to compare survival among groups. Comparison of lung recovery among the three groups was also performed. ResultsLung recovery rates were 29.7% (15,670 of 52,747), 19.4% (3879 of 20,040), and 18.1% (704 of 3898) for groups I, II, and III, respectively. The 1-, 3-, and 5-year recipient survival rates were 86.2%, 69.2%, and 55.7% for group I; 84.9%, 66.9%, and 53.8% for group II; and 85.5%, 65.3%, and 50.3% for group III, respectively (adjusted P = .25; multivariate Cox regression method). When group I was used as reference, the adjusted hazard ratio for group II was 1.04 (95% CI, 0.98-1.10) and for group III, it was 1.08 (95% CI, 0.96-1.23), after adjusting with the multivariate Cox regression model. ConclusionsThere was no significant difference in lung recipient survival. The lung recovery rate from donors with abnormal kidney function was lower compared with that of donors with normal kidney function.

Association of neighborhood-level social determinants of health with psychosocial distress in patients newly diagnosed with lung cancer.

Patients with lung cancer experience high rates of psychosocial distress. They are also more likely to have unresolved, unmet social needs which may contribute to psychosocial distress. Despite this, neighborhood-level social determinants of health (SDOH) in relation to psychosocial distress have not been adequately investigated in patients with lung cancer. The goal of this study is to examine the association between neighborhood-level SDOH and psychosocial distress among a sample of newly diagnosed patients with lung cancer. This cross-sectional study included newly diagnosed, adult lung cancer patients from an accredited cancer center. Psychosocial distress was measured with the Distress Thermometer. Neighborhood-level SDOH indicators for income and education were used to create a composite SDOH variable categorized into low, medium, and high deprivation levels. Covariates were age, gender, race/ethnicity, comorbidity index, cancer stage, and insurance status. Using multivariate logistic regression modeling, the association of psychosocial distress with the neighborhood-level SDOH was examined. The prevalence of psychosocial distress in the sample was 58.4%. Neighborhood-level SDOH indicators were not significantly associated with psychosocial distress. Higher odds of psychosocial distress were significantly associated with being female and having distant or regional cancer versus localized cancer. The age group 66-75 years was significantly associated with lower distress compared with those aged <65 years. Psychosocial distress was consistently high across all the SDOH deprivation categories; but these neighborhood-level SDOH indicators do not appear to be predictive of psychosocial distress at the time of diagnosis of lung cancer.

Bronchoalveolar lavage improved ventilation/perfusion matching in pediatric severe mycoplasma pneumoniae pneumonia with lung consolidation.

A 15-year-old girl was admitted to our Pediatric Intensive Care Unit (PICU) due to respiratory failure and septic shock. She was intubated and mechanically ventilated and received vasoactive drugs therapy. Chest CT scan showed opacities in both lungs with marked consolidation in the right (figure 1A). Saline contrast-enhanced electrical impedance tomography (EIT) was conducted with 10 ml 5% NaCl bolus injection through the central venous catheter.1 Significant reductions in ventilation and perfusion were observed in the right dorsal regions (figure 2A). Shunt percentage was much higher in the dorsal regions. The patient received bedside bronchoalveolar lavage with fiberoptic bronchoscope therapy in PICU. The airway mucosa was congested, edematous and diffusely hemorrhagic. White mucus plugs were observed in the right airway, especially in the basal segment of the right lower lobe. The terminal bronchioles (generations 5-7) were completely blocked (figure 3A-B). A total of 100 ml sterilized isotonic saline was instilled in five aliquots and the lavage fluid and sputum were sucked out subsequently with 100 mmHg negative pressure after each insufflation (figure 3C-D). The bronchoalveolar lavage fluid next-generation sequencing test suggested that the pathogen was mycoplasma pneumoniae and the patient was treated with levofloxacin. After receiving bronchoscopy and bronchoalveolar lavage for three consecutive days, bedside EIT measurement suggested improvements of ventilation and perfusion in the right dorsal regions (figure 2B). Shunt percentage was significantly reduced. The findings were coincided with subsequent CT scans (figure 1B). The patient was successfully weaned from ventilator 1 day after last bronchoalveolar lavage. To our knowledge, this is the first clinical report to evaluate the efficacy of bronchoalveolar lavage on regional ventilation and perfusion at the bedside in severe mycoplasma pneumoniae pneumonia with lung consolidation. In severe mycoplasma pneumoniae pneumonia, about 24.9% patients were accompanied with lung consolidation. Fiberoptic bronchoscopy and bronchoalveolar lavage therapy can help detecting mycoplasma pneumoniae pneumonia pathogen in time, with detecting infection, locating sputum plug and inflammatory polyps, and improving consolidation. 22 However, a real-time bedside tool for evaluating the effectiveness of bronchoalveolar lavage in PICU was still missing. Saline-bolus based EIT evaluating the ventilation-perfusion matching has been implemented in adult lung diseases. 1,31,3 This case shows that EIT has the potential to identify regional ventilation and perfusion defects in the lesion areas, as well as to evaluate the corresponding improvement after bronchoalveolar lavage. No side effects were observed after the 10 ml 5% NaCl bolus injection. Further studies are warranted to confirm the clinical use of EIT in bronchoalveolar lavage in various pediatric age group and lung diseases This article is protected by copyright. All rights reserved.

Lung epithelium development and airway regeneration.

The lung is composed of a highly branched airway structure, which humidifies and warms the inhaled air before entering the alveolar compartment. In the alveoli, a thin layer of epithelium is in close proximity with the capillary endothelium, allowing for an efficient exchange of oxygen and carbon dioxide. During development proliferation and differentiation of progenitor cells generates the lung architecture, and in the adult lung a proper function of progenitor cells is needed to regenerate after injury. Malfunctioning of progenitors during development results in various congenital lung disorders, such as Congenital Diaphragmatic Hernia (CDH) and Congenital Pulmonary Adenomatoid Malformation (CPAM). In addition, many premature neonates experience continuous insults on the lung caused by artificial ventilation and supplemental oxygen, which requires a highly controlled mechanism of airway repair. Malfunctioning of airway progenitors during regeneration can result in reduction of respiratory function or (chronic) airway diseases. Pathways that are active during development are frequently re-activated upon damage. Understanding the basic mechanisms of lung development and the behavior of progenitor cell in the ontogeny and regeneration of the lung may help to better understand the underlying cause of lung diseases, especially those occurring in prenatal development or in the immediate postnatal period of life. This review provides an overview of lung development and the cell types involved in repair of lung damage with a focus on the airway.

Relationship of Exercise Capacity, Physical Function, and Frailty Measures With Clinical Outcomes and Healthcare Utilization in Lung Transplantation: A Scoping Review.

Background.Measures of exercise capacity, frailty, and physical function are commonly used in lung transplant candidates and recipients to evaluate their physical limitations and the effects of exercise training and to select candidates for transplantation. It is unclear how these measures are related to clinical outcomes and healthcare utilization before and after lung transplantation. The purpose of this scoping review was to describe how measures of exercise capacity, physical function, and frailty are related to pre- and posttransplant outcomes.Methods.We considered studies of any design that included performance-based tests of exercise capacity, physical function, and frailty in adult lung transplant candidates or recipients. Outcomes of interest were clinical outcomes (eg, mortality, quality of life) and healthcare utilization.Results.Seventy-two articles met the inclusion criteria. The 6-min walk test (6MWT) was shown to be related to mortality on the waiting list with different distance values as cutoffs points. There were inconsistent results regarding the relationship of the 6MWT with other clinical outcomes. Few studies have examined the relationship between the cardiopulmonary exercise test or the short physical performance battery and clinical outcomes, although some studies have shown relationship with survival posttransplant and quality of life. Few studies examined the relationship between the tests of interest and healthcare utilization‚ and the results were inconsistent.Conclusions.Except for the relationship between the 6MWT and mortality on the waiting list, there is limited evidence regarding the relationship of performance-based measures of exercise capacity, frailty, and physical function with clinical outcomes or healthcare utilization.

Small for gestational age is associated with reduced lung function in middle age: A prospective study from first to fifth decade of life.

The association between birth weight, particularly relative to gestational age, and adult lung function is uncertain. We investigated the associations between birth weight relative to gestational age and measures of lung function in middle age, and mediation of these associations by adult height. Participants in the Tasmanian Longitudinal Health Study who had both known birth weight and lung function assessment at age 45 years were included (n=849). Linear regression models were fitted to investigate the association between small for gestational age and birth weight with post-bronchodilator lung function measures (forced expiratory volume in 1 second [FEV1 ], forced vital capacity [FVC], FEV1 /FVC, diffusing capacity for carbon monoxide [DL co], residual volume [RV] and total lung capacity [TLC]), adjusting for potential confounders. The contribution of adult height as a mediator of these associations was investigated. Compared with infants born with normal weight for gestational age, those born small for gestational age had reduced FEV1 (coefficient: -191 ml [95%CI: -296, -87]), FVC (-205 ml [-330, -81]), TLC (-292 ml [-492, -92]), RV (-126 ml [-253, 0]) and DL co (-0.42 mmol/min/kPa [-0.79, -0.041]) at age 45 years. However, they had comparable FEV1 /FVC. For every 1kg increase in birth weight, lung function indices increased by an average of 117 ml (95%CI: 40, 196) for FEV1 , 124 ml (30, 218) for FVC, 215 ml (66, 365) for TLC and 0.36 mmol/min/kPa (0.11, 0.62) for DL co, independent of gestational age, but again not for FEV1 /FVC. These associations were significantly mediated by adult height (56%-90%). Small for gestational age was associated with reduced lung function that is likely due to smaller lungs with little evidence of any specific parenchymal impairment.

The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-ninth adult lung transplantation report-2022; focus on lung transplant recipients with chronic obstructive pulmonary disease.

The International Society for Heart and Lung Transplantation (ISHLT) International Thoracic Organ Transplant (TTX) Registry has gathered data regarding transplant procedures, donor and recipient characteristics, and outcomes from a global community of transplant centres over the last 3 decades. Close to 70,000 adult lung transplant procedures have been reported to the Registry since its initiation, each providing an opportunity for a recipient with end-stage lung disease to regain quality of life and longevity.

Transcriptomic-Metabolomic Profiling in Mouse Lung Tissues Reveals Sex- and Strain-Based Differences

Omics analyses are commonly used for identifying pathways and genes responsible for physiologic and pathologic processes. Though sex is considered a biological variable in rigorous assessments of pulmonary responses to oxidant exposures, the contribution of the murine strain is largely ignored. This study utilized an unbiased integrated assessment of high-resolution metabolomic profiling and RNA-sequencing to explore sex- and strain-dependent pathways in adult mouse lungs. The results indicated that strain exhibited a greater influence than sex on pathways associated with inflammatory and oxidant/antioxidant responses and that interaction metabolites more closely resembled those identified as differentially expressed by strain. Metabolite analyses revealed that the components of the glutathione antioxidant pathway were different between strains, specifically in the formation of mixed disulfides. Additionally, selenium metabolites such as selenohomocystiene and selenocystathionine were similarly differentially expressed. Transcriptomic analysis revealed similar findings, as evidenced by differences in glutathione peroxidase, peroxiredoxin, and the inflammatory transcription factors RelA and Jun. In summary, an multi-omics integrated approach identified that murine strain disproportionately impacts baseline expression of antioxidant systems in lung tissues. We speculate that strain-dependent differences contribute to discrepant pulmonary responses in preclincal mouse models, with deleterious effects on clinical translation.

Lung function in young adults born small for gestational age at term.

See related Editorial

Exercise adaptations in COPD: the pulmonary perspective.

In chronic obstructive pulmonary disease (COPD), the progressive loss of lung tissue is widely considered irreversible. Thus, various treatment and rehabilitation schemes, including exercise-based pulmonary rehabilitation (PR) are thought to slow down but not reverse or halt the disease. Nonetheless, the adult lung conceals the intrinsic capacity for de novo lung tissue formation in the form of abundant progenitor/stem cell populations. In COPD, these maintain their differentiation potential but appear to be halted by a state of cellular senescence in the mesenchyme, which normally functions to support and coordinate their function. We propose that notably high-intensity interval training may improve pulmonary gas exchange during exercise in patients with COPD by interrupting mesenchymal senescence, thus reestablishing adaptive angiogenesis. By means of this, the downward spiral of dyspnea, poor quality of life, physical inactivity, and early death often observed in COPD may be interrupted. If this is the case, the perception of the regenerative capacity of the lungs will be fundamentally changed, which will warrant future clinical trials on various exercise schemes and other treatments targeting the formation of new lung tissue in COPD.

Risk Factors and Outcomes of Postoperative Hepatic Dysfunction After Lung Transplantation

BackgroundHepatic dysfunction is a morbid complication of lung transplantation. Little is known about risk factors for postoperative hepatic dysfunction or its impact on survival after lung transplantation. MethodsThis retrospective analysis of 1406 adult lung transplant recipients was performed at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania between January 1, 2007 and December 1, 2019. Patients were excluded for redo lung transplantation, concomitant cardiac surgery, or concurrent solid organ transplantation. Postoperative liver dysfunction was classified as either ischemic liver injury or nonischemic dysfunction (transaminitis, hyperbilirubinemia). ResultsAmong the 1155 primary lung transplant recipients included, postoperative hepatic dysfunction developed in 96 (8.3%) after lung transplantation. A history of liver disease was the greatest predictor of postoperative hepatic dysfunction (odds ratio, 6.19; CI, 2.13-17.4; P < .001). Patients with postoperative hepatic dysfunction had a greater need for intraoperative blood products (ischemic, 12 U [range, 6-21 U]; nonischemic, 10 U [range, 4-28 U]; vs none, 4 U [range, 1-12 U]; P < .001) and an increased need for postoperative circulatory support (ischemic, 16 [76%]; nonischemic, 25 [33%]; none, 117 [11%]; P < .001). Both ischemic liver injury and nonischemic dysfunction were associated with diminished 1-, 3-, and 5-year term survival (ischemic, 27.5%, 16.5%, and 0%, respectively; nonischemic, 60%, 49.6%, and 46.9%, respectively; none, 87.3%, 72.3%, and 59.5%, respectively; P < .001). ConclusionsHepatic dysfunction after lung transplantation is associated with significant morbidity and mortality. A history of liver disease was the best positive predictor for postoperative dysfunction. Additional studies are necessary to identify the best treatment algorithm to avoid hepatic dysfunction more effectively in the postoperative setting after lung transplantation.

Factors associated with middle-aged adult obstructive lung function deficits in the grass pollen season

BACKGROUND AND AIM: Impact of grass pollen season (GPS) on lung function is not well-studied at a community level. We assessed this in middle-aged participants from the Tasmanian Longitudinal Health Study (TAHS), and potential modifiers of this association. METHODS: Spirometry was performed at the TAHS 53-year follow-up (n=2478). We compared lung function for those tested in the GPS (Oct-Jan) to those tested outside GPS using linear regression. Interactions were investigated for: questionnaire-reported asthma, hay fever, eczema and grass pollen allergy symptoms in the past 12 months; traffic-related air pollution (TRAP) exposure defined by living &amp;#x3c;200m from a major road; and glutathione S-transferase (GST) polymorphisms (GSTM1, GSTT1, GSTP1) for a subsample. RESULTS: An association between GPS and reduced lung function was observed among those with allergic disease, also those living &amp;#x3c;200m from major roads or with a GSTM1 genotype (p for interaction&amp;#x2264;0.1). Participants with current asthma tested in the GPS had increased mid- to small-airway obstruction compared to out of GPS, with zFEV₁/FVC ratio = -0.3 (95% CI = -0.6,-0.1) and zFEF25-75% = -0.4 (95% CI= -0.6,-0.07). Similar evidence of obstruction was observed in current hay fever, eczema, grass pollen allergy or living &amp;#x3c;200m from major roads. A modest association was found with bronchodilator responsiveness = 18 ml (95% CI = -18,54) in those with GSTM1 null genotypes. CONCLUSION: Middle-aged adults with allergic disease or TRAP exposure may be more susceptible to obstructive lung function deficits during the grass pollen season. Genetics may also play a role, but further research on this is required. KEY WORDS: Asthma, air pollution, eczema, grass pollen, genetics, lung function

Post-Transplantation Anemia and Risk of Death Following Lung Transplantation

Post-transplantation anemia (PTA) is frequent among solid organ transplant recipients and has been associated with increased morbidity and mortality. However, the prevalence and impact of PTA in lung transplant recipients is still not elucidated. We performed a retrospective cohort study of adult Danish lung transplant recipients between January 2010 and December 2019. The prevalence and severity of PTA were determined during the first three years post-transplantation. Associations between PTA and selected risk factors were established using uni- and multivariate logistic regression models. A total of 278 patients were included. At one and three years post-lung transplantation the prevalence of PTA was 75% and 52%, respectively. Male sex was associated with increased odds of PTA at all time points (aOR ranging from 2.3, 95% CI 1.1-4.6, P=0.02 to 5.9, 95% CI 2.6-14, P < .001). Cystic fibrosis was also associated with anemia at one-year post-transplantation (aOR 4.3, 95% CI 1.2-17, P=0.03). We found no strong associations between PTA and renal function or viral infections. Excess mortality in recipients with moderate or severe anemia compared to patients with mild or no anemia was borderline statistically significant at one-year post-lung transplantation (aHR 2.0, 95% CI 0.9-4.4, P = 0.07). Post-transplantation anemia is very common in Danish lung transplant recipients. Male sex and cystic fibrosis are independent risk factors for development of anemia. Further investigation on PTA, the underlying mechanisms, and its clinical impact is needed.

Mechanical properties of the premature lung: From tissue deformation under load to mechanosensitivity of alveolar cells.

Many preterm infants require mechanical ventilation as life-saving therapy. However, ventilation-induced overpressure can result in lung diseases. Considering the lung as a viscoelastic material, positive pressure inside the lung results in increased hydrostatic pressure and tissue compression. To elucidate the effect of positive pressure on lung tissue mechanics and cell behavior, we mimic the effect of overpressure by employing an uniaxial load onto fetal and adult rat lungs with different deformation rates. Additionally, tissue expansion during tidal breathing due to a negative intrathoracic pressure was addressed by uniaxial tension. We found a hyperelastic deformation behavior of fetal tissues under compression and tension with a remarkable strain stiffening. In contrast, adult lungs exhibited a similar response only during compression. Young’s moduli were always larger during tension compared to compression, while only during compression a strong deformation-rate dependency was found. In fact, fetal lung tissue under compression showed clear viscoelastic features even for small strains. Thus, we propose that the fetal lung is much more vulnerable during inflation by mechanical ventilation compared to normal inspiration. Electrophysiological experiments with different hydrostatic pressure gradients acting on primary fetal distal lung epithelial cells revealed that the activity of the epithelial sodium channel (ENaC) and the sodium-potassium pump (Na,K-ATPase) dropped during pressures of 30 cmH2O. Thus, pressures used during mechanical ventilation might impair alveolar fluid clearance important for normal lung function.

Altered Expression of Pulmonary Epithelial Cell Markers in Fetal and Adult Mice Generated by in vitro Embryo Culture and Embryo Transfer

Lung development is impaired in mice generated through transfer of in vitro-derived blastocysts. The main objective of the current study was to determine if the composition of epithelial cells in the fetal and adult lung tissue is altered in mice generated through transfer of in vitro-derived blastocysts. The study comprised two experimental (EGs) and two control (CGs) groups. Fetuses (18.5 d.p.c.) and adult mice (8 weeks old) of the EGs (EG_fetus, n = 18; EG_adult, n = 15) were produced by the transfer of day 5 F2 blastocysts to pseudo-pregnant females. F2 fetuses and adult mice derived from naturally ovulating females served as the CGs (CG_fetus, n = 18; CG_adult, n = 15). The expression of Tuba-1a (a marker of ciliated cells), Foxj-1 (a marker of motile ciliated cells), Uch-L1 (a marker of neuroendocrine cells), Cldn-10 (a marker of club cells), Aqp-5 (a marker of type I alveolar cells), and Sp-C (a marker of type II alveolar cells) was determined using Western blot, immunohistochemistry/immunofluorescence, and quantitative RT-PCR analyses. Weight of fetuses as well as adult mice is decreased in mice comprising the EGs. Impaired lung development observed in EG_fetus was associated with altered expression of Tuba-1a, Foxj-1, Cldn-10, Uch-L1, Sp-C, and Aqp-5. Morphology of the adult lung tissue was similar between the groups except for a significant increase in the thickness of the epithelia in EG_adult. The expression of Cldn-10 and Sp-C was also altered in EG_adult. It remains to be determined whether altered expression of these genes has any long-term impact on epithelial cell functions in the adult lung tissue.

EP14.05-023 Characterization of Real-World Use of Lurbinectedin in Adult Small Cell Lung Cancer Patients in the United States

Lurbinectedin received accelerated FDA approval in June 2020 for treatment of adult patients with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was based on a single-arm, phase 2 trial, which demonstrated an overall response rate of 35.2%, a duration of response of 5.3 months, and a manageable safety profile. This study explored patient characteristics and treatment patterns of patients treated with lurbinectedin during the 16 months after approval in the United States (US).

Human alveolar progenitors generate dual lineage bronchioalveolar organoids

Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280+/EpCAM+ population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3β inhibitor, CHIR99021. By RNA-seq profiling of GSK-3β knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction.

Developmental basis of evolutionary lung loss in plethodontid salamanders.

One or more members of four living amphibian clades have independently dispensed with pulmonary respiration and lack lungs, but little is known of the developmental basis of lung loss in any taxon. We use morphological, molecular, and experimental approaches to examine the Plethodontidae, a dominant family of salamanders, all of which are lungless as adults. We confirm an early anecdotal report that plethodontids complete early stages of lung morphogenesis: Transient embryonic lung primordia form but regress by apoptosis before hatching. Initiation of pulmonary development coincides with expression of the lung-specification gene Wnt2b in adjacent mesoderm, and the lung rudiment expresses pulmonary markers Nkx2.1 and Sox9. Lung developmental-genetic pathways are at least partially conserved despite the absence of functional adult lungs for at least 25 and possibly exceeding 60 million years. Adult lung loss appears associated with altered expression of signaling molecules that mediate later stages of tracheal and pulmonary development.