Adult Lung Research Articles

Humoral and T-cell response 12 months after the first BNT162b2 vaccination in solid organ transplant recipients and controls: Kinetics, associated factors, and role of SARS-CoV-2 infection.

We investigated humoral and T-cell responses within 12 months after first BNT162b2 vaccine in solid organ transplant (SOT) recipients and controls who had received at least three vaccine doses. Furthermore, we compared the immune response in participants with and without previous SARS-CoV-2 infection. We included adult liver, lung, and kidney transplant recipients, and controls were selected from a parallel cohort of healthcare workers. At 12th-month, the IgG geometric mean concentrations (GMCs) (P<0.001), IgA GMCs (P=0.003), and median IFN-γ (P<0.001) were lower in SOT recipients than in controls. However, in SOT recipients and controls with previous infection, the neutralizing index was 99%, and the IgG, and IgA responses were comparable. After adjustment, female-sex (aOR: 3.6, P<0.009), kidney (aOR: 7.0, P= 0.008) or lung transplantation (aOR: 7.5, P= 0.014), and use of mycophenolate (aOR: 5.2, P=0.03) were associated with low IgG non response. Age (OR:1.4, P=0.038), time from transplantation to first vaccine (OR: 0.45, P<0.035), and previous SARS-CoV-2 infection (OR: 0.14, P<0.001), were associated with low IgA non response. Diabetes (OR:2.4, P=0.044) was associated with T-cell non response. In conclusion, humoral and T-cell responses were inferior in SOT recipients without previous SARS-CoV-2 infection but comparable to controls in SOT recipients with previous infection.

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15−/− mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate.

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of invivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.

Adult congenital horseshoe lung with bilateral pulmonary sequestration: A case report

Horseshoe lung (HL) is an infrequent congenital lung anomaly. Its main feature is that the lower lungs on both sides extend behind the pericardium and fuse across the midline, usually accompanied by pulmonary dysplasia. It is reported that 80% of HL is relevant to the abnormal return of some pulmonary veins from the right lung to the inferior vena cava or right atrium (scimitar syndrome). Most patients are within 5years old, most commonly within 1 year old, but HL may also have no apparent clinical symptoms or mild symptoms. This case is a 36-years-old adult female who developed left chest pain more than a month ago and continued to worsen for 10days. The patient also had repeated pulmonary infection with cough and expectoration.

Functionalized zein nanoparticles targeting neonatal Fc receptor to enhance lung absorption of peptides

Peptides have a distinguished therapeutic potential for several chronic conditions, and more than 80 peptides exist in the global market. However, most of these marketed peptide drugs are currently delivered intravenously or subcutaneously due to their fast degradation and limited absorption through non-invasive routes. The pulmonary route is favored as a non-invasive route. Neonatal Fc receptor (FcRn) is expressed in adult human lungs and has a role in enhancing the pulmonary absorption of monoclonal antibodies. In this work, we developed and characterized candidate protein delivery systems for the pulmonary administration of peptides. The prepared bare and loaded zein nanoparticles (ZNPs), targeted, physically, and covalently PEGylated ZNPs showed hydrodynamic diameters between 137 and 155 nm and a narrow distribution index. Insulin, which was used as a protein model, showed an association efficiency of 72%, while the FcRn-targeted peptide conjugation efficiency was approximately 68%. The physically adsorbed poloxamer 407 on insulin-loaded ZNPs showed slower and controlled insulin release. The in vitro cell culture model consists of the NCI-H441 epithelial cell line, which confirmed its expression of the targeted receptor, FcRn. The safety of ZNPs was verified after incubation with both cell lines of the in vitro pulmonary model, namely NCI-H441 and HPMEC-ST1.6R, for 24 h. It was observed that targeted ZNPs enhanced insulin permeability by showing a higher apparent permeation coefficient than non-targeted ZNPs. Overall, both targeted PEGylated ZNPs showed to be suitable peptide carriers and adequately fit the demands of delivery systems designed for pulmonary administration.Graphical

Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis.

Transient, tissue-specific, embryonic progenitors are important cell populations in vertebrate development. In the course of respiratory system development, multipotent mesenchymal and epithelial progenitors drive the diversification of fates that results to the plethora of cell types that compose the airways and alveolar space of the adult lungs. Use of mouse genetic models, including lineage tracing and loss-of-function studies, has elucidated signaling pathways that guide proliferation and differentiation of embryonic lung progenitors as well as transcription factors that underlie lung progenitor identity. Furthermore, pluripotent stem cell-derived and ex vivo expanded respiratory progenitors offer novel, tractable, high-fidelity systems that allow for mechanistic studies of cell fate decisions and developmental processes. As our understanding of embryonic progenitor biology deepens, we move closer to the goal of in vitro lung organogenesis and resulting applications in developmental biology and medicine.

KRT5+/p63+ Stem Cells Undergo Senescence in the Human Lung with Pathological Aging.

Adult lungs present high cellular plasticity against stress and injury, mobilizing stem/progenitor populations from conducting airways to maintain tissue homeostasis and gas exchange in alveolar spaces. With aging, pulmonary functional and structural deterioration occurs, mainly in pathological conditions, which is associated with impaired stem cell activity and increased senescence in mice. However, the impact of these processes underlying lung physiopathology in relation to aging has not been explored in humans. In this work, we analyzed stem cell (SOX2, p63, KRT5), senescence (p16INK4A, p21CIP, Lamin B1) and proliferative (Ki67) markers in lung samples from young and aged individuals, with and without pulmonary pathology. We identified a reduction in SOX2+ cells but not p63+ and KRT5+ basal cells in small airways with aging. In alveoli, we revealed the presence of triple SOX2+, p63+ and KRT5+ cells specifically in aged individuals diagnosed with pulmonary pathologies. Notably, p63+ and KRT5+ basal stem cells displayed colocalization with p16INK4A and p21CIP, as well as with low Lamin B1 staining in alveoli. Further studies revealed that senescence and proliferation markers were mutually exclusive in stem cells with a higher percentage colocalizing with senescence markers. These results provide new evidence of the activity of p63+/KRT5+ stem cells on human lung regeneration and point out that regeneration machinery in human lung is activated under stress due to aging, but fails to repair in pathological cases, as stem cells would likely become senescent.

Clinical characteristics and treatment strategy of nocardiosis in lung transplant recipients: A single-center experience

Nocardia are infrequent pathogens that disproportionately afflict organ transplant recipients. The present study aimed to summarize the clinical manifestations, diagnostic approaches, and treatment strategies of nocardiosis in lung transplant recipients. This retrospective study reviewed the clinical data of adult lung transplant recipients who were complicated with nocardiosis between January 2018 and December 2021 at the largest lung transplant center in South China. The incidence of nocardiosis was 4.2% (13/316), including 9 cases of pulmonary nocardiosis and 4 disseminated nocardiosis (blood, pulmonary and intracranial). The accuracy in diagnosing nocardiosis was 77.8% by culture and 100% by metagenomic next-generation sequencing (mNGS). Nocardia farcinica was the most common causative pathogen. Trimethoprim-sulfamethoxazole-based combination therapy was administered initially, followed by a single antibiotic as the maintained therapy, lasting for 4-8 months. mNGS is more accurate than culture in diagnosing nocardiosis. Most patients responded well to the antibiotic therapy with combined antibiotics at the initial stage followed by a single antibiotic treatment.

953: INFLAMMATORY MYOFIBROBLASTIC TUMOR PRESENTING AS A LUNG NODULE: A CASE REPORT

Introduction: Inflammatory Myofibroblastic Tumors are a group of soft tissue neoplasms constituting a mixture of spindle-shaped myofibroblasts or fibroblasts and a variable amount of inflammatory cells with a predilection for the lung often presenting with non-specific symptoms. They represent less than 1% of adult lung tumors. Histopathologic and immunohistochemical analysis of a biopsy specimen is the mainstay of diagnosis. Description: A 30-year-old male presented to the ER with flank pain and episodes of small volume hemoptysis intermittently for the last six years. At presentation, a computed tomography angiography (CTA) of the chest revealed a cavitary nodule of 24 mm at the largest diameter containing rounded soft tissue mass arising adjacent to the right posterior basal segmental bronchus along with adjacent ground glass airspace opacities likely reflecting pulmonary haemorrhage which was confirmed on bronchoscopy revealing fresh blood emanating from the posterior basal segment of the right lower lobe with no endobronchial lesion. Bronchoalveolar lavage (BAL) of the segment was performed with cultures ultimately turning negative. At a later date, a robot-assisted navigational bronchoscopy-guided transbronchial needle aspiration of the lesion was performed. Histopathology results were significant for spindle cells arranged in a storiform to a haphazard pattern. The spindle cells had basophilic cytoplasm and elongated nuclei with fine chromatin. Immunostains of the tumor cells were positive for CD56, CD68, and CD34 (focal), SMA and ALK and negative for cytokeratins AE1/AE3, CK8/18, TTF-1, synaptophysin, chromogranin, S100, desmin, and CD117, SS18-SSX, STAT6, HHV-8, SOX10, CD30, and langerin. These findings supported the diagnosis of an inflammatory myofibroblastic tumor. Discussion: Chest imaging is crucial for early identification. Complete surgical excision provides long-term survival benefits, preventing local recurrence and metastasis. Corticosteroids can be used when the mass is unresectable. If ALK-1 is positive, crizotinib is beneficial in some cases. Our case highlights the need for further investigative studies to establish the natural history of this neoplastic disease and discover appropriate medical management for it.

82. Incidence rates of invasive aspergillosis among lung transplant recipients in timeperiods with universal and targeted antifungal prophylaxis - a nationwide cohort study

Abstract Background The best stategy for prevention of invasive aspergillosis (IA) after lung transplantation (LTX) has not been determined. In 2016, Danish guidelines for IA prophylaxis was changed from 12 weeks of universal prophylaxis with voriconazole to targeted prophylaxis with posaconazole and inhaled amphotericin B for high risk patients. In a previous study we found significantly higher rates of adverse events in the period with universal prophylaxis. The objectives of this study were to compare rates of IA 1) in time periods before and after change of guidelines; 2) during persontime on vs. persontime without antifungal prophylaxis in the total study period. Methods In a Danish nationwide study we included all adult lung transplant recipients (LTXr), 2010–2019. Proven and probable IA were defined using ISHLT criteria. Patients were censored at the first of following events: death, retransplantation, end of 2019, or one year after LTX. The cumulative hazard of IA was calculated using the Nelson Aalen estimator. Rates of IA were analyzed in bi- and multivariate Poisson regression models adjusted for the time period after LTX (0–6 and 6–12 months). Persontime on protocol prophylaxis (start to end + 14 days) was treated as time-updated variable. Results A total of 295 LTXr were followed for 245 person-years, of whom 183/193 vs. 6/102 initiated antifungal prophylaxis during the universal vs. the targeted prophylaxis period (Table 1). IA was diagnosed in 34/193 (17.6%) vs. 15/102 (14.7%) LTXr the first year after transplantation in the universal vs. targeted prophylaxis period. Overall, similar cumulative hazards of IA were observed between the universal and targeted prophylaxis period (p=0.59, Figure 1). The adjusted incidence rate ratio (aIRR) of IA during the universal vs. targeted prophylaxis period was 1.30 (95% CI 0.69–2.44), (Table 2). In the total study period, the aIRR of IA during persontime on vs. persontime without antifungal prophylaxis was 0.87 (95% CI 0.40–1.88), (Table 2). Characteristics of lung transplant recipients in time periods with universal voriconazole and targeted posaconazole and inhaled amphotericin B prophylaxis. Proven and probable invasive aspergillosis including anastomosis infection, trakeobronkitis and pneumonia according to ISHLT criteria. *) Underlying diseases categorized as high risk of invasive aspergillosis. Incidence rates (IR) and incidence rate ratios (IRR) of invasive aspergillosis in lung transplant recipients in two multivariate models. Poisson regression models comparing rates of IA in model 1) during universal prophylaxis time period versus targeted prophylaxis time period and in model 2) during persontime on prophylaxis (start to end + 14 days) versus persontime without prophylaxis in the total study period 2010–2019. Adjusted for time after LTX IRR: Bivariable model including the listed variables in bold and adjustment for time after transplantation (time-updated). Fully adjusted IRR: Multivariable model with adjustment for sex, age, high risk underlying disease, single/double lung transplant, Aspergillus prior to transplantation and time after transplantation (time-updated). Abbreviations: LTX = lung transplant recipients; CI = confidence interval; IR = incidence rates per 100 person-years; IRR = incidence rate ratio; Ref. = reference. Cumulative hazards of invasive aspergillosis the first year after lung transplantation in time periods with universal voriconazole versus targeted posaconazole and inhaled amphotericin B prophylaxis. Conclusion A strategy of targeted prophylaxis, for high risk patients only, may be preferred over universal voriconazole prophylaxis after LTX due to similar rates of IA and lower rates of adverse events. Disclosures Maiken C. Arendrup, DMSci, PhD, MD, Chiesi, Gilead: Honoraria|F2G, Cidara, Scynexis: Grant/Research Support Michael Perch, MD, Boeringer-Ingelheim: Travel grant|PulmonX: Expert Testimony|Roche: Grant/Research Support|Takeda: Expert Testimony|Therakos: Honoraria|Zambon: Advisor/Consultant|Zambon: Expert Testimony Marie Helleberg, PhD, DMSc, AstraZeneca: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Janssen: Advisor/Consultant|Roche: Advisor/Consultant|Sobi: Advisor/Consultant.

Can birth weight predict offspring’s lung function in adult age? Evidence from two Swedish birth cohorts

BackgroundAssociations between birth weight (BW) and adult lung function have been inconsistent and limited to early adulthood. We aimed to study this association in two population-based cohorts and explore if BW, adjusted for gestational age, predicts adult lung function. We also tested adult lung function impairment according to the mis-match hypothesis—small babies growing big as adults.MethodsWe included 3495 individuals (aged 46.4 ± 5.4 years) from the Malmo Preventive Project (MPP), Sweden, born between 1921 and 1949, and 1401 young to middle-aged individuals (aged 28.6 ± 6.7 years) from the Malmo Offspring Study (MOS) with complete data on BW and gestational age. Adult lung function (forced vital capacity [FVC], forced expiratory volume in one second [FEV1] and the FEV1/FVC-ratio) were analysed as level of impairment (z-score), using multiple linear and logistic regressions.ResultsBW (z-score) did not predict adult lung function in MPP, whereas BW was a significant (p = 0.003) predictor of FEV1 following full adjustment in MOS. For every additional unit increase in BW, children were 0.77 (95% CI 0.65–0.92) times less likely to have impaired adult lung function (FEV1). Moreover, adults born with lower BW (< 3510 g) showed improved lung function (FEV1 and FEV1/FVC in MOS and MPP, respectively) if they achieved higher adult body weight.ConclusionsAdults born with lower birth weight, adjusted for gestational age, are more likely to have impaired lung function, seen in a younger birth cohort. Postnatal growth pattern may, however, compensate for low birth weight and contribute to better adult lung function.

Exploring pulmonary distribution of intratracheally instilled liquid foams in excised porcine lungs

The applicability of inhalation therapy to some severe pulmonary conditions is often compromised by limited delivery rates (i.e. total dose) and low deposition efficiencies in the respiratory tract, most notably in the deep pulmonary acinar airways. To circumvent such limitations, alternative therapeutic techniques have relied for instance on intratracheal liquid instillations for the delivery of high-dose therapies. Yet, a longstanding mechanistic challenge with such latter methods lies in delivering solutions homogeneously across the whole lungs, despite an inherent tendency of non-uniform spreading driven mainly by gravitational effects. Here, we hypothesize that the pulmonary distribution of instilled liquid solutions can be meaningfully improved by foaming the solution prior to its instillation, owing to the increased volume and the reduced gravitational bias of foams. As a proof-of-concept, we show in excised adult porcine lungs that liquid foams can lead to significant improvement in homogenous pulmonary distributions compared with traditional liquid instillations. Our ex-vivo results suggest that liquid foams can potentially offer an attractive novel pulmonary delivery modality with applications for high-dose regimens of respiratory therapeutics.

Pneumologie meets Pädiatrie

In pediatrics and adult respiratory medicine different lung diseases play different roles. Asthma is one of the most frequent respiratory diseases worldwide and can be newly manifested across all ages, from childhood to senior age; however, asthma symptoms can also resolve at any time and the disease can go into remission. Pediatricians and adult respiratory physicians have different perceptions and approaches towards the meaning of terms such as asthma remission and the importance of certain biomarkers as well as towards the use of lung function in the diagnostic process. Diseases, such as chronic obstructive pulmonary disease or cystic fibrosis, that until recently were exclusively represented in either pediatrics or adult respiratory medicine, now necessitate that both specialist disciplines more closely approach each other both on a scientific level and in clinical care.

Awareness of hazards due to tobacco among people aged 15 years and older in Chongqing, China, in 2020: A cross-sectional analysis.

Tobacco smoke contains a large number of harmful substances and carcinogens. Smoking and secondhand smoke cause a variety of cancers and diseases, seriously endangering human health. However, the status and characteristics of the awareness of hazards due to tobacco among people aged ≥15 years in Chongqing, China, are still unknown. A multistage stratified cluster random sampling method was used to select ten districts and counties in Chongqing Municipality, China and a total of 6622 people were investigated between August and October 2020. The chi-squared test was used to analyze the awareness of hazards due to tobacco in various populations after the data had been cleaned and weighted. In 2020, the awareness rates of people aged ≥15 years in Chongqing, China, about a specific disease caused by smoking were lung cancer (77.1%), heart disease (45.1%), stroke (40.1%), and penile erectile dysfunction (24.2%). However, only 22.1% of the respondents knew that smoking could simultaneously lead to all four diseases mentioned above. Adult lung cancer was the disease with the highest awareness rating (72.5%), followed by children's lung disease (54.2%) and adult heart disease (46.1%). A total of 42.0% of respondents knew that secondhand smoke could cause the three diseases simultaneously. Only 22.0% of those correctly understood the harm of low-tar cigarettes. The logistic regression results showed that education level and occupation were risk factors for lack of awareness of hazards due to tobacco. In contrast, media campaigns on tobacco control were a protective factor. The awareness of hazards due to tobacco among people aged ≥15 years in Chongqing, China, still needs to be improved. More graphic health warning labels and mass media campaigns about the hazards of tobacco should be carried out to raise people's awareness and warn about the health risks of smoking.

COVID-19 in pediatric lung transplant recipients: Clinical course and outcome

COVID-19 causes high morbidity and mortality in adult lung transplant (LTX) recipients. Data on COVID-19 in children after LTX is limited. We report the clinical presentation and outcome of SARS-CoV-2 infection in 19 pediatric LTX recipients. Between March 2020 and June 2022, SARS-CoV-2 testing was performed on all pediatric LTX patients with COVID-19 symptoms or contact with a SARS-CoV-2 infected person. Positive patients were prospectively evaluated for symptoms, treatment and outcome. Vaccination status and immune response were recorded. Nineteen out of 51 pediatric LTX recipients had a SARS-CoV-2 infection. Mean age was 12.3 years (IQR 9-17), 68% were female, 84% had preexisting comorbidities. Mean time between LTX and SARS-CoV-2 infection was 4.8 years (IQR 2-6). No patients experienced severe COVID-19: 11% were asymptomatic, and 89% had mild symptoms, primarily rhinitis (74%), fever (47%), and cough (37%). One SARS-CoV-2 positive patient was hospitalized due to combined fungal and bacterial infection. Mean duration of symptoms was 10.5 days (IQR 3-16), whereas mean period of positivity by antigen test was 21 days (IQR 9-27, p=0.013). Preventive antiviral therapy was initiated in 3 patients. After a mean follow-up of 2.5 months (IQR 1.1-2.4), no patient reported persistent complaints related to COVID-19. Lung function tests remained stable. Unlike adult LTX recipients, children and adolescents are at low risk for severe COVID-19, even with risk factors beyond immunosuppression. Our findings cast doubt on the necessity of excessive isolation for these patients and should reassure clinicians and caregivers of LTX patients.

Niche-Dependent Regulation of Lkb1 in the Proliferation of Lung Epithelial Progenitor Cells

Lung homeostasis and regeneration depend on lung epithelial progenitor cells. Lkb1 (Liver Kinase B1) has known roles in the differentiation of airway epithelial cells during embryonic development. However, the effects of Lkb1 in adult lung epithelial progenitor cell regeneration and its mechanisms of action have not been determined. In this study, we investigated the mechanism by which Lkb1 regulates lung epithelial progenitor cell regeneration. Organoid culture showed that loss of Lkb1 significantly reduced the proliferation of club cells and alveolar type 2 (AT2) cells in vitro. In the absence of Lkb1, there is a slower recovery rate of the damaged airway epithelium in naphthalene-induced airway epithelial injury and impaired expression of surfactant protein C during bleomycin-induced alveolar epithelial damage. Moreover, the expression of autophagy-related genes was reduced in club cells and increased in AT2 cells, but the expression of Claudin-18 was obviously reduced in AT2 cells after Lkb1 knockdown. On the whole, our findings indicated that Lkb1 may promote the proliferation of lung epithelial progenitor cells via a niche-dependent pathway and is required for the repair of the damaged lung epithelium.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

Niche-mediated repair of airways is directed in an occupant-dependent manner.

In injured airways of the adult lung, epithelial progenitors are called upon to repair by nearby mesenchymal cells via signals transmitted through the niche. Currently, it is unclear whether repair is coordinated by the mesenchymal cells that maintain the niche or by the airway epithelial cells that occupy it. Here, we show that the spatiotemporal expression of Fgf10 by the niche is primarily orchestrated by the niche's epithelial occupants-both those that reside prior to, and following, injury. During homeostasis, differentiated airway epithelial cells secrete Sonic hedgehog (Shh) to inhibit Fgf10 expression by Gli1+ peribronchial mesenchymal cells in the niche. After injury, remaining epithelial cells produce Wnt7b to induce Fgf10 expression in airway smooth muscle cells in the niche. We find that this reliance on a common activator of airway epithelial stem cells also allows for the recruitment of remote stem cell populations when local populations have been exhausted.

Cryoablation in lung transplantation: Its impact on pain, opioid use, and outcomes

ObjectiveTo assess the effect of intraoperative cryoablation on postoperative patient-reported pain, opioid use, and clinical outcomes in lung transplantation. MethodsWe performed a single-center retrospective cohort study of adult lung transplant recipients from August 2017 to September 2018. We compared outcomes of patients who received intraoperative cryoablation of the intercostal nerves with those who did not. Primary outcomes were postoperative patient-reported pain scores and opioid use. Secondary outcomes included postoperative sedation and agitation levels and perioperative outcomes. Data were abstracted from patients' electronic health records. ResultsOf the 102 patients transplanted, 45 received intraoperative cryoablation (intervention group) and 57 received the standard of care, which did not include intercostal or serratus blocks or immediate postoperative epidural placement (control group). The intervention group had significantly lower median and maximum postoperative pain scores at days 3 and 7 and significantly lower oral opioid use at days 3, 7, and 14 compared with the control group. Chronic opioid use at 3 and 6 months' posttransplant was lower in the intervention group. Differences in perioperative outcomes, including length of mechanical ventilation, sedation and agitation levels, and hospital stay, were not clinically meaningful. Survival at 30 days and 1 year was superior in the intervention compared with the control group. ConclusionsFindings suggest that use of intraoperative cryoablation is an effective approach for treating pain and reducing opioid use in patients who undergo lung transplant, but a randomized study across multiple institutions is needed to confirm these findings.

Living Donor Lobar Lung Transplant for a Patient With Lung Disease Caused by ABCA3 Gene Mutations: A Case Report

Recessive gene mutations in ABCA3 cause lethal neonatal respiratory distress, and pediatric and adult interstitial lung disease. The effectiveness of medical treatments is limited and a subset of such patients will eventually require lung transplantation. A 20 months old boy developed interstitial lung disease and was treated with hydroxychloroquine, which had a significant effect. Sequence analysis of ABCA3 gene revealed newly discovered compound heterozygous mutations. His respiratory dysfunction gradually progressed over years and he underwent living-donor lobar lung transplantation (LDLLT) at 8 years of age with his parents serving as bilateral lobar donors. The parents had been genetically examined beforehand and found to be carriers who had one allele with an ABCA3 gene mutation and the other with no mutation. The recipient has been well without chronic lung allograft dysfunction and his parents have been enjoying healthy social lives for 7 years since the operations. LDLLT appears to be a valid option for selected children with ABCA3 gene mutations who are too ill to wait for cadaveric lung transplantation. When relatives of the recipient with ABCA3 gene mutation are deemed potential donors for LDLLT, sequence analyses of the donors are indispensable to exclude the possibility that they are late-onset patients of this recessive hereditary disease.