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Background: Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to the thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface liquid (ASL) and impairs mucociliary transport function in cystic fibrosis patients. Hypothesis: We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Methods: ATP12A expression level was evaluated by immunohistochemical staining and RNAscope in situ hybridization in normal and IPF human distal lungs. Primary human small airway culture model was used to elucidate the potential roles of ATP12A in the activation of latent TGF-beta activation. Viral vector mediated ATP12A overexpression was used in the bleomycin-induced lung fibrosis mouse model. A potassium-competitive proton pump blocker, vonoprazan was used to block ATP12A functions both in vitro and in vivo. Results: Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. Potassium competitive proton pump blocker vonoprazan decreased airway surface liquid (ASL) pH and TGF-β1 activation in IPF small airway epithelial cells. In addition, overexpression of the ATP12A protein in mouse lungs worsened the Bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan. Conclusion: Those data support that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF. This work was funded by the National Institutes of Health (HL153165-01A1 to X.L.), the Cystic Fibrosis Foundation (LI19XX0), Cystic Fibrosis Research Institute, and Spectrum Health-MSU Alliance Corporation funds. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

IPF is a condition in which an injury to the lung leads to the accumulation of scar tissue. This fibrotic tissue reduces lung compliance and impairs gas exchange. Studies have shown that infection with COVID-19 significantly worsens the clinical outcomes of IPF patients. The exact etiology of IPF is unknown, but recent evidence suggests that the distal small airways, (those having a diameter less than 2 mm in adults), play a role in the early pathogenesis of IPF. TGF-β1 is a main driver of fibrosis in a variety of tissues; the binding of TGF-β1 to its receptor triggers a signaling cascade that results in inflammatory signaling, accumulation of collagen and other components of the extracellular matrix, and immune system activation. This study aimed to investigate possible mechanisms that contribute to worsening lung fibrosis in IPF patients after being diagnosed with COVID-19, with a particular focus on the role of TGF-β1. Small airway cell cultures derived from IPF and post-COVID-19 IPF patient transplant tissues were submitted for RNA-sequencing and differential gene expression analysis. The genetic signatures for each disease state were determined by comparing the differentially expressed genes present in the cells cultured under control conditions to cells cultured with TGF-β1. The genes shared between the culture conditions laid the framework for determining the genetic signatures of each disease. Our data found that genes associated with pulmonary fibrosis appeared to be more highly expressed in the post-COVID fibrosis samples, under both control and TGF-β1-treated conditions. A similar trend was noted for genes involved in the TGF-β1 signaling pathway; the post-COVID fibrosis cell cultures seemed to be more responsive to treatment with TGF-β1. Gene expression analysis, RT-PCR, and immunohistochemistry confirmed increased levels of BMP signaling in the IPF small airway cell cultures. These findings suggest that TGF-β1 signaling in IPF small airway cells could be inhibited by BMP signaling, leading to the differences in genetic signatures between IPF and post-COVID fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in cystic fibrosis patients. We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened the bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan (VON). This data supports the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.

Background Gastroesophageal reflux disease (GERD) is associated with chronic lung allograft dysfunction after lung transplant. Treating GERD after lung transplant has been shown to improve lung allograft function. This case series describes the efficacy of the Stretta procedure to control GERD after lung transplant at our institution. Methods Eleven patients underwent the Stretta procedure at our institution for GERD after lung transplant during the years 2016-2017. Pre- and post-Stretta reflux parameters were gathered. Pulmonary function was followed up until subsequent fundoplication surgery, death, or end of study observation. Results Reflux on esophagram was noted in 9 patients before Stretta and 8 patients after Stretta. The median number of acid reflux events was 31.5 vs. 26 after Stretta ( P = .95), and median percent time in reflux was 17.7% before vs. 14.5% after Stretta ( P = .76). Median DeMeester score before Stretta was 65.5 (range: 33.2-169.8) vs. 42.5 (range: 19.2-109.8) after the procedure ( P = .14). Median lower esophageal resting pressure was 20.7 mm Hg (n = 7) compared to 25.9 mm Hg (n = 9) on post-Stretta follow-up ( P = .99). Median FEV1% predicted was 84% (41-97%) before compared to 71% (23-108%) at 1 year after the procedure ( P = .14). Seven patients required fundoplication surgery for continued reflux. All patients were on triple immunosuppression, most commonly prednisone, tacrolimus, and mycophenolate (n = 9). Discussion The Stretta procedure did not provide expected results at our institution after lung transplant surgery. Based on our limited series, we do not recommend routine use of the Stretta procedure for management of GERD in lung transplant patients.

Purpose Highly sensitized recipients remain a challenge in lung transplantation. There are no standardized protocols among lung transplant centers to guide management of these patients. Some centers choose not to transplant highly sensitized patients due to the risk of graft dysfunction and death. We describe our center's experience and outcomes managing lung transplant recipients with positive flow-cytometric prospective cross matches (FXM). Methods We retrospectively analyzed patients who underwent lung transplantation with positive FXM from August 2015 to November 2019. Outcomes included overall length of stay, 1-year survival, graft function at one year, and incidence of antibody mediated rejection (AMR) and CLAD (BOS). Results There were 11 patients with FXM (6 females, 5 males; 6 with restrictive lung disease, 3 with obstructive lung disease, 1 with cystic fibrosis, and 1 with pulmonary vascular disease). 7 (63%) had concomitant positive virtual cross matches. 10 (91%) were managed with high-dose IVIg alone immediately post-op. 3 patients additionally received intra and/or post-op plasma exchange, rituximab and/or bortezimab. Median length of hospital stay was 50 days. Median length of follow up is 30 months (range 11-63 months). KM estimate of one-year survival was 90%. Clinical episodes of AMR requiring treatment occurred in 1 (9%) patient at 3 years post-transplant. DSA cleared in 8 patients (73%). Infections occurred in 5 patients (45%). None were life threatening. CLAD grade ≥ 1 occurred in only 2 patients (18%), one at 1.5 years and the other 3 years post-transplant. FEV1 at one year was >89% of personal best in all patients. Conclusion Successful lung transplantation of highly sensitized recipients is feasible. Using our center's approach results in longer hospital stay but excellent one-year outcomes. Further study is needed to identify patients at risk for graft dysfunction and death due to AMR who benefit from early aggressive treatment, and to avoid unnecessary treatment in lower risk patients.

SESSION TITLE: Transplantation Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Chronic lung allograft dysfunction (CLAD) remains the leading cause of long-term mortality after lung transplantation (LTX) with no proven therapeutic strategies except re-transplantation Anecdotal reports suggest a role for the lymphocyte depleting agent, Alemtuzumab (AL), an anti-CD52 monoclonal antibody We reviewed our experience with AL for the treatment of refractory CLAD METHODS: Eight consecutive LTX recipients were identified AL was given as a single subcutaneous dose of 30 mg Cell-cycle inhibitor therapy was held and valganciclovir and azole prophylaxis were given for at least 6 months after AL treatment The slope of FEV1 3 months before and after AL were compared Complications of AL therapy including infections and survival were assessed RESULTS: The cohort consisted of 5 males and 3 females with a median age at time of AL administration of 66 y (range: 50-72) Time post-transplant was 2 43 y (range: 1 4-5 4) Pre-transplant diagnoses were COPD (n=3), and 1 each of CF, bronchiectasis (immotile cilia syndrome), IPF, PVOD and IPAH All subjects were bilateral recipients and 1 was post-left pneumonectomy early after transplant All had a predominantly obstructive CLAD phenotype, stages 4 (N=2), 3 (N=4), 2 (N=1) and 1 (N=1) with rapid loss of lung function The median slope of decline in FEV1 in the 3 months prior to AL was -336ml/m (range: -39 to -552) compared with +24 ml/m (range: -171 to +48) during the 3 months post AL administration (P = 0 016) No acute reactions to AL treatment were observed Clinically symptomatic infections occurred in 4 patients following AL Community acquired respiratory viral infections were observed in 2 (parainfluenza and coronavirus on 2 separate occasions in 1 patient and rhinovirus in another) Pseudomonas tracheobronchitis developed in 1 These infections were considered mild-moderate One subject developed new parenchymal opacities with isolation of Rasamsonia argillacea and Mycobacterium fortuitum Two patients died due to progressive CLAD 3 and 6 months after AL The other six are alive at a median follow-up time of 12 months (range: 7 – 20) Kaplan-Meier survival estimate at one year was 75% At last follow-up, CLAD stages among survivors was 4 (N=1), 3 (N=4) and 2 (N=1) CONCLUSIONS: AL therapy was associated with a significant attenuation in lung function decline in lung transplant recipients with rapidly progressive CLAD Treatment was generally well tolerated with few serious infection complications CLINICAL IMPLICATIONS: AL should be considered for rapidly progressive CLAD Randomized controlled trials are required to establish efficacy and safety DISCLOSURES: No relevant relationships by Reda Girgis, source=Web Response No relevant relationships by Ryan Hadley, source=Web Response no disclosure submitted for Anupam Kumar;No relevant relationships by Cameron Lawson, source=Web Response no disclosure on file for Marzia Leacche;No relevant relationships by Jennifer McDermott, source=Web Response no disclosure on file for Edward Murphy;No relevant relationships by Gayathri Sathiyamoorthy, source=Web Response