Soma Jyothula

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate “libraries” of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.

Background: Lung transplantation can provide quality of life and survival benefits for patients with coronavirus disease 2019 (COVID-19)–associated end-stage lung disease. Characteristics and outcomes of these lung transplant recipients are limited to mostly single-center experiences or provide a short-term follow-up.Methods: Characteristics of deceased donors and adult lung transplant recipients for COVID-19–associated end-stage lung disease between August-2020 and June-2022 were analyzed using deidentified United Network for Organ Sharing database. Post-transplant patient survival of COVID-19 recipients was analyzed and compared with non–COVID-19 recipients. Secondary outcomes were length of hospitalization, post-transplant complications, and rates of organ rejection.Results: During the study period, 400 lung transplants for COVID-associated end-stage lung disease comprised 8.7% of all lung transplants performed in United States. In the COVID-19 group, Hispanic males received lung transplants at significantly higher rates. The COVID-19 group was younger and had greater need for intensive care unit stay, mechanical ventilation, hemodialysis, extracorporeal membrane oxygenation support, and receipt of antibiotics pre-lung transplant. They had higher lung allocation score, with a shorter wait-list time and received more double lung transplants compared with non–COVID-19 recipients. Post-transplant, the COVID-19 cohort had longer hospital stays, with similar 1-year patient survival (COVID, 86.6% vs non–COVID, 86.3%). Post-transplant, COVID-19–associated deaths were 9.2% of all deaths among lung transplant recipients.Conclusions: Lung transplantation offers a effective option for carefully selected patients with end-stage lung disease from prior COVID-19, with short-term and long-term outcomes similar to those for lung transplant recipients of non–COVID-19 etiology.

Background: A significant proportion of patients with severe and persistent coronavirus disease 2019 (COVID-19) require continuous ventilatory support and occasional extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS). Lung transplantation is a treatment option for patients who develop severe ARDS. Methods: Our lung transplant database was retrospectively reviewed for patients who underwent lung transplantation for COVID-19 pulmonary disease at Memorial Hermann Hospital, Texas Medical Center, Houston, Texas, from January 2020 to March 2022. We evaluated outcomes of patients who were followed in our clinic at least 6 months post-transplant. Pretransplant patient characteristics, COVID-19-related treatment, histopathology results, and postdischarge course were evaluated. Results: Among a total of 13 lung transplant recipients, 6 consecutive patients were identified who had a minimum of 6 months of follow-up post–lung transplantation. The average age of patients was 55 years, with a male predominance. The median time to transplantation was 111 days. All 6 patients had significant postinfectious complications due to COVID-19 before transplant. Histopathological findings from explanted lungs showed a predominance of fibrotic change. There were no reported cases of rejection or graft dysfunction. 5 patients had minimal to no post-transplant infectious complications. One patient died 218 days post-transplant from infectious complications. Conclusions: Five out of six lung transplant recipients at our institution have demonstrated excellent long-term outcomes after index hospitalization, for a mean follow-up of 13 months post–lung transplantation. Lung transplantation for lung fibrosis due to COVID-19 is an acceptable salvage treatment option. Larger studies are warranted to confirm these findings.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional coactivators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin-treated (BLM-treated) mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 ( Trf1 ) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis, as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression, and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter–driven luciferase assay demonstrated direct binding of Six1 to the 5′-TCAGG-3′ consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis and providing a potentially novel pathway for targeting in IPF therapy.

Severe pulmonary hypertension (PH) in obese patients pose a challenge to treat despite advances in medical therapeutics. Current treatment options are limited for patients who are not responding to maximal medical therapy. Here, we present a case of multifactorial PH, not responsive to ambrisentan, tadalafil, and treprostinil, even after optimization of cardiac and pulmonary function and had a poor prognosis. She demonstrated weight loss after bariatric surgery, improving her restrictive lung disease, obstructive sleep apnea and PH, and overall functionality. Bariatric surgery may offer a potential therapeutic option, in patients with morbid obesity and PH resistant to maximal medical therapy.