Ekroop Dhillon

Background/objectives: Transplant-related pulmonary fibrosis (TPF) occurs after allogeneic hematopoietic cell transplant and after lung transplantation. Effective therapies that prevent or reverse established transplant-related airway fibrosis remain limited. Human cell-based models are valuable for initial drug screening, but complementary in vivo models are needed to evaluate treatment responses in the presence of an allogeneic graft, an intact recipient immune system, systemic drug exposure, and multicellular tissue remodeling. This study evaluated murine orthotopic tracheal transplantation (OTT) as a practical in vivo platform for antifibrotic drug testing, using pirfenidone as a benchmark antifibrotic intervention. Methods: C57BL/6J mice underwent syngeneic or allogeneic OTT and received vehicle or pirfenidone (250 mg/kg daily) from day 21 to 30 posttransplant. Explanted grafts were analyzed for the expression of alpha-smooth muscle actin (α-SMA), fibronectin 1 (Fn1), collagen type I alpha 1 chain (Col1a1), and tenascin C (Tnc) by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Total collagen content was assessed by measuring hydroxyproline levels using a colorimetric hydroxyproline assay. Results: Pirfenidone normalized the expression of α-SMA, Fn1, Col1a1 and Tnc to levels comparable to those of syngeneic controls and significantly reduced hydroxyproline (p < 0.0001). Conclusions: Using pirfenidone as a benchmark antifibrotic, the murine OTT model detected concordant treatment-associated reductions in profibrotic gene expression and collagen content. These findings support the feasibility and pharmacodynamic responsiveness of OTT as an in vivo platform for secondary-stage antifibrotic drug testing. Additional investigational therapies will be required to establish the broader generalizability and predictive performance of the platform.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease caused by Aspergillus fumigatus (Af), prevalent in persons with cystic fibrosis (CF) or asthma. In ABPA, Af proteases drive a T-helper cell-2 (Th2)-mediated allergic immune response leading to inflammation that contributes to permanent lung damage. Corticosteroids and antifungals are the mainstays of therapies for ABPA. However, their long-term use has negative sequelae. The treatment of patients with CF (pwCF) has been revolutionized by the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Pharmacological improvement in CFTR function with highly effective elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes of pwCF. The mechanism behind the improvement in patient outcomes is a continued topic of investigation as our understanding of the role of CFTR function evolves. As ETI therapy gains traction in CF management, understanding its potential impact on ABPA, especially on the allergic immune response pathways and Af infection becomes increasingly crucial for optimizing patient outcomes. This literature review aims to examine the extent of these findings and expand our understanding of the already published research focusing on the intersection between ABPA therapeutic approaches in CF and the rapid impact of the evolving CFTR modulator landscape. While our literature search yielded limited reports specifically focusing on the role of CFTR modulator therapy on CF-ABPA, findings from epidemiologic and retrospective studies suggest the potential for CFTR modulator therapies to positively influence pulmonary outcomes by addressing the underlying pathophysiology of CF-ABPA, especially by decreasing inflammatory response and Af colonization. Thus, this review highlights the promising scope of CFTR modulator therapy in decreasing the overall prevalence and incidence of CF-ABPA.