Targeting ATP12A, a Nongastric Proton Pump α Subunit, for Idiopathic Pulmonary Fibrosis Treatment.

Idiopathic pulmonary fibrosis (IPF) is a pathological condition of unknown etiology that 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 lung disease. The ATP12A gene encodes the α-subunit of the nongastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in patients with cystic fibrosis. It is hypothesized that the ATP12A protein may play a role in the pathogenesis of IPF. The authors' studies demonstrate that ATP12A protein is overexpressed in distal small airways from the lungs of patients with IPF compared with normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened bleomycin induced experimental pulmonary fibrosis. This was prevented by a potassium competitive proton pump blocker, vonoprazan. These data support the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has potential as a novel therapeutic strategy in IPF treatment.

Renal replacement therapy prior to liver transplant and inpatient mortality in patients without advanced kidney disease: A nationwide study.

Background and Aim: The utility of renal replacement therapy (RRT) before liver transplant (LT) in patients without end-stage renal disease (ESRD) or advanced chronic kidney disease (CKD-IV/V) is debatable and lacks data support. We aimed to evaluate the impact of RRT on patients undergoing LT. Methods: We used the National Readmission Database (2016-2019) to identify all index hospitalizations undergoing RRT before LT (cases). A matched comparison cohort of similar hospitalizations without RRT before LT was identified (controls) after 1:1 propensity score matching for age, gender, and available comorbidities. Results: We matched 364 cases (RRT before LT) to 364 controls (LT without prior RRT). There was no statistical difference in all-cause inpatient mortality (4.9% vs 3.6% P = 0.4). A significantly greater proportion of cases were associated with ICU admission (40.7% vs 17.0%, P < 0.001) and RRT requirement post LT (100% vs 17%, P < 0.001). There was no difference in 30- (hazard ratio [HR] 1.1, 0.4-2.6), 60- (HR 0.9, 0.4-1.8), or 90-day (HR 0.8, 0.4-1.6) inpatient mortality between the groups. Also, 180-day survival estimates were comparable (P = 0.5). The results were similar in patients with no chronic kidney disease (CKD) and CKD-III. Conclusion: RRT prior to LT, in patients without advanced CKD or ESRD, was associated with greater instances of ICU stay and need for future RRT. Also, 30-, 60-, and 90-day inpatient mortality rates were similar, and 180-day survival estimates were comparable.

Differential Transcriptomic Signatures of Small Airway Cell Cultures Derived from IPF and COVID-19-Induced Exacerbation of Interstitial Lung Disease.

Idiopathic pulmonary fibrosis (IPF) is a pathological condition wherein lung injury precipitates the deposition of scar tissue, ultimately leading to a decline in pulmonary function. Existing research indicates a notable exacerbation in the clinical prognosis of IPF patients following infection with COVID-19. This investigation employed bulk RNA-sequencing methodologies to describe the transcriptomic profiles of small airway cell cultures derived from IPF and post-COVID fibrosis patients. Differential gene expression analysis unveiled heightened activation of pathways associated with microtubule assembly and interferon signaling in IPF cell cultures. Conversely, post-COVID fibrosis cell cultures exhibited distinctive characteristics, including the upregulation of pathways linked to extracellular matrix remodeling, immune system response, and TGF-ß1 signaling. Notably, BMP signaling levels were elevated in cell cultures derived from IPF patients compared to non-IPF control and post-COVID fibrosis samples. These findings underscore the molecular distinctions between IPF and post-COVID fibrosis, particularly in the context of signaling pathways associated with each condition. A better understanding of the underlying molecular mechanisms holds the promise of identifying potential therapeutic targets for future interventions in these diseases.

Treatment of Gastroesophageal Reflux Disease After Lung Transplant Using Radiofrequency Ablation to the Lower Esophageal Sphincter (Stretta Procedure).

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.

Identification of micromonolactam, a new polyene macrocyclic lactam from two marine Micromonospora strains using chemical and molecular methods: clarification of the biosynthetic pathway from a glutamate starter unit.

Through a combination of chemical and molecular analysis, a new polyene macrolactam named micromonolactam was obtained from two marine-derived Micromonospora species. This new polyene metabolite is a constitutional isomer of salinilactam A but contains a different polyene pattern and one cis double bond, in contrast to the all trans structure reported for salinilactam A. The molecular analysis data also established that micromonolactam is a hybrid polyketide derived from 11 polyketide units and a modified glutamate starter unit.