Multiple cell types have been implicated in pathogenesis of pulmonary fibrosis with pericytes emerging as a new focus due to their role in promoting fibrotic remodeling. Fibrotic environment changes normal pericyte functions, but transcriptional programs regulating pericyte transition towards fibrotic state remain unclear. Utilizing single cell RNA-sequencing of human pulmonary fibrotic lungs and mouse genetic models, we identified a unique cluster of fibrosis-associated pericytes which was not present in normal lungs and exhibited a distinctive transcriptional signature indicating transition of normal pericytes to a fibrotic state. FOXF1 was identified as one of the transcription factors decreased in fibrotic pericytes. Pericyte-specific deletion of Foxf1 increased severity of pulmonary fibrosis in bleomycin mouse model as demonstrated by reduced survival, impaired lung functions, increased body weight loss and increased fibrotic remodeling. Pericyte-specific overexpression of Foxf1 attenuated pulmonary fibrosis, reversed fibrotic changes and improved survival outcomes. Based on single cell RNA-sequencing and chromatin immunoprecipitation sequencing, FOXF1 transcriptionally regulates an extensive pericyte signaling network critical for pulmonary fibrosis. In vitro, FOXF1 transcriptionally activated ID3 which inhibited fibroblast activation through decreased secretion of IL8 and CXCL1 by pericytes. Altogether, FOXF1 prevents transition of pericytes to a fibrotic state, suggesting new therapeutic opportunities for treatment of pulmonary fibrosis.

Small extracellular vesicles (sEVs) isolated from plasma of lung transplant recipients (LTRs) with chronic lung allograft dysfunction (CLAD) contain increased levels of lung associated self-antigens, Kα1 tubulin and collagen V, and decreased expression of the tumor suppressor liver kinase B1 (LKB1). In this study, sEVs were isolated from plasma collected from LTRs with or without cystic fibrosis (CF) from multiple centers at the onset of CLAD and 6 and 12 months before clinical diagnosis of CLAD (n = 32) as well as from time-matched stable controls (n = 25). sEVs were analyzed for Kα1 tubulin, collagen V, and LKB1 by western blot. Exoview R200, a functionalized microarray chip was employed to characterize the LKB1 in sEVs. EVs from non-CF LTRs had higher levels of lung self-antigens (p < 0.05) and lower levels of LKB1 (p = 0.024) 12 months before CLAD diagnosis than those from time-matched stable LTRs; however, in CF LTRs, only LKB1 levels were lower (p = 0.0005) 6 months before diagnosis. Further characterization of sEVs 6 months before CLAD in CF LTRs also demonstrated significantly lower numbers of LKB1 and LKB1/CD9 + sEV particles. Reduced LKB1 in circulating sEVs offers a potential biomarker for the risk of CLAD in LTRs with CF.

Background: Laparoscopic antireflux surgery (LARS) is widely used to treat gastroesophageal reflux disease (GERD). Iatrogenic gastroesophageal injuries, when recognized intraoperatively, can be managed without major consequences, whereas undetected injuries presenting as postoperative leaks are associated with high morbidity and mortality. Despite their complexity, research on post-LARS leaks is scant. We aim to describe the diagnosis and management of such injuries at a tertiary referral center. Methods: We describe a single-center case series of patients referred for gastroesophageal perforations after LARS. Patients were identified through the personal records of surgeons at our institution. A narrative literature review was conducted to summarize publications on the topic. Results: Five patients (four female [80%]; median age, 73 years [IQR, 67–74]) were included. The median time between LARS and clinical presentation was 2 (IQR, 1–8) days (range 1–15 days). The most frequent symptoms were shortness of breath (all five patients) and pain (three [60%] patients). All patients presented with hypoxia, and four (80%) patients presented with sepsis. Two (40%) patients underwent primary repair, and three (60%) required limited esophagogastrectomy without immediate reconstruction. All patients required both thoracic and abdominal exploration, and all of them experienced significant postoperative complications (Clavien–Dindo ≥ 3). The median hospital stay was 58 days (IQR, 34–59). At a median follow-up of 14 months (IQR, 6–28), all patients were alive. Conclusions: Although infrequent, gastroesophageal perforation after LARS often requires complex surgical interventions and prolonged hospital stays. Additional efforts should focus on prevention and early recognition.

An increasing number of patients with a history of bariatric surgery and advanced respiratory disease are presenting for lung transplantation (LTx). We aimed to describe and compare LTx outcomes between recipients with prior bariatric surgery and a matched control group at a high-volume lung transplant center. After IRB approval, we identified bilateral LTx recipients with a pre-LTx history of bariatric surgery (Roux-en-Y gastric bypass [RYGB], sleeve gastrectomy [SG], or laparoscopic adjustable gastric band [LAGB]). The institutional experience is reported as a case series. Furthermore, perioperative and mid-term transplant outcomes such primary graft dysfunction (PGD), antibody-mediated rejection (AMR), acute cellular rejection (ACR), chronic lung allograft dysfunction (CLAD)-free survival, and overall survival (OS) were compared to a 1-to-2 propensity score-matched control group. Nine patients (median age: 65 years; 77.8

BACKGROUND:We compared trends and outcomes of lung transplant recipients who were bridged to transplantation using mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO) during the new Composite Allocation Score (CAS) era or the previous Lung Allocation Score (LAS) era. METHODS:The United Network for Organ Sharing database was queried for all adult lung transplant recipients bridged to transplant with MV or ECMO during the LAS (April 5, 2005 to August 3, 2023) or CAS (September 3, 2023 to September 30, 2024) era. Baseline patient characteristics, perioperative outcomes, and short-term survival were compared between eras. RESULTS:A total of 2982 patients were included: 1866 with ECMO-bridge (LAS-ECMO: 1597; CAS-ECMO: 269) and 1116 with MV-bridge (LAS-MV: 1072; CAS-MV: 44). MV-bridge use was higher during LAS than CAS (LAS, 2.9% vs. CAS, 0.8%, p < 0.001), whereas ECMO-bridge was higher in the CAS era (LAS, 4.3% vs. CAS, 5.3%, p = 0.03). Recipient age was higher for both MV-bridge and ECMO-bridge cohorts in the CAS era. Median waitlist times were shorter, and median ischemic time and donor organ travel distances were longer in the CAS era for both MV and ECMO cohorts. Perioperative outcomes and 30-day and 90-day survival were comparable between eras. Waitlist mortality and delisting rates for medical deterioration were lower in the CAS era. CONCLUSIONS:Rates of ECMO-bridge to transplant increased in the CAS era compared to the LAS era. Although the donor lung travel distances were longer, perioperative outcomes were comparable to those of the LAS era. Long-term outcomes of BTT candidates in the CAS era remain to be seen.

BACKGROUND:The prevalence of elderly patients undergoing lung transplantation continues to increase. We aimed to explore outcomes of lung transplantation in older age groups. METHODS:Records of patients undergoing bilateral lung transplantation at a single institution from April 13, 2007, to March 7, 2023, were retrospectively reviewed. Patient characteristics and outcomes were compared by univariate and multivariate methods. RESULTS:A total of 970 patients were identified: 480 (49.5%), 277 (28.6%), 191 (19.7%), and 22 (2.3%) were aged 15 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 79 years, respectively. Older groups showed increasing rates of male sex, White race, and restrictive lung disease (P < .001). Younger recipients required ventilatory support at listing more often (P < .001). Postoperatively, younger groups had shorter lengths of stay but higher rates of extracorporeal membrane oxygenation at 72 hours (P < .001). One-year survival was similar in the age groups of 15 to 64 years, 65 to 69 years, and 70 to 74 years. The age group of 15 to 64 years had the highest median survival (15-64 years, 6.10 years; 65-69 years, 4.78 years; 70-74 years, 4.65 years; 75-79 years, 4.46 years; P < .001). The 5-year survival rate was 58.0%, 46.8%, 44.5%, and 47.2% for patients aged 15 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 79 years, respectively. CONCLUSIONS:Recipients aged 65 years and older and their younger counterparts had similar short-term outcomes. Advanced recipient age was associated with less favorable but acceptable long-term survival. In addition, the age groups of 65 to 69 years, 70 to 74 years, and 75 to 79 years had similar short- and long-term outcomes. Careful selection of older recipients is associated with improved perioperative outcomes and short-term survival.

BACKGROUND:The pHoenix score (pHx-S) is a simple pH-monitoring metric developed to improve gastroesophageal reflux disease (GERD) diagnosis by integrating upright and supine acid exposure time (AET) to reduce "inconclusive" cases compared to AET alone. Since the pHx-S was derived from 48-h wireless studies, we aimed to validate its use in transnasal catheter-based 24-h pH monitoring. METHODS:We conducted a single-center, cross-sectional study of patients undergoing 24-h pH monitoring for suspected GERD (2016-2024). Diagnostic cutoffs for the pHx-S were ≤ 7.06 (normal), 7.06-8.45 (inconclusive), and ≥ 8.45 (pathological). Its predictive performance was validated against the DeMeester score (DMS) and compared to total AET. We also evaluated the impact of meal period inclusion/exclusion on the DMS, AET, and pHx-S. RESULTS:Of 318 individuals (199 [62.6%] women; median age, 58 [46-67] years), 170 (53.5%) presented with pathological acid exposure based on DMS. Using total AET alone, 150 (47.2%), 35 (11%), and 133 (41.8%) were classified as normal, inconclusive, and pathological, respectively. Using the pHx-S, 148 cases (46.5%) were classified as normal and 155 (48.7%) as pathological. Notably, only 15 cases (4.7%) were considered borderline using the pHx-S, a 57.1% reduction (p = 0.015) compared to total AET. Sensitivity/specificity of the pHx-S were 97.6%/97.3% (lower threshold) and 91.2%/100% (upper threshold). Inclusion/exclusion of meals had minimal impact on diagnosis by DMS, AET, or pHx-S. CONCLUSIONS:The pHx-S improves GERD diagnosis by reducing inconclusive cases, simplifying the calculation, accounting for the disease spectrum, and eliminating the need for meal recording compliance with comparable accuracy to the DMS.

Biomechanical damage to the respiratory epithelium by acidic refluxate and endopeptidases (such as activated pepsin) are thought to be key mechanisms by which gastroesophageal reflux disease (GERD) contributes to the development and worsening of chronic respiratory disorders. These chronic disorders include chronic cough, asthma, suppurative lung diseases, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis (IPF). In such patients, acid suppression therapy to treat GERD and associated respiratory symptoms has produced controversial results, as these treatments decrease the acidity of the refluxate but do not prevent gastroesophageal reflux and aspiration itself. Consequently, mechanical control of GERD through laparoscopic and endoscopic procedures is a plausible option to halt the progression of such chronic respiratory disorders. This article provides an overview of GERD diagnosis and therapeutic alternatives (i.e., pharmacological therapy, antireflux surgery, and other minimally invasive procedures) in the context of advanced pulmonary disease, particularly IPF.

Purpose:To investigate the relationship between Public Health Service (PHS) increased-risk donors and post-lung transplant (LT) Kaposi sarcoma (KS). Methods:This retrospective cohort study included LT recipients (April 1, 2019-April 1, 2024) who had PHS increased-risk donors at our institution. Data were abstracted from UNOS and electronic medical records. Published post-LT KS cases were also reviewed. Descriptive statistics and Kaplan-Meier estimates were used. Results:Of 467 LT recipients, 90 (23.9%) had PHS increased-risk donors, including 13 [14.4%] men who have sex with men (MSM). Four of these 13 (30.8%) recipients developed KS (median time to diagnosis, 365 days [IQR 276-502]). Basiliximab was the most common induction agent; all 4 patients were on standard 3-drug immunosuppression. All 4 recipients had pulmonary KS without extrapulmonary involvement and positive human herpes virus 8 (HHV-8) immunohistochemistry results. Pulmonary nodules were incidentally noted on chest CT in 3 asymptomatic patients; 1 patient presented with dyspnea and central airway obstruction. Immunosuppression was reduced and mTOR inhibitors were initiated for all 4 patients; 1 patient underwent stenting of the left main bronchus and radiation, and 1 was treated with liposomal doxorubicin. Three recipients improved, and 1 is awaiting follow-up imaging (median follow-up, 276 days [IQR 177-433]). In our data pooled with 15 published cases, mean survival time was lower in patients with disseminated KS (182 vs. 563 days, p=0.011). Conclusion:LT recipients with MSM donors may be at an increased risk for post-LT KS from donor-derived HHV-8. Larger, more definitive, multicenter studies are needed.

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines—Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors—Ccr2 and Ccr5—in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines—TNF-α; IL-6 and chemokine receptor—CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19. Graphical Abstract