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Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of the interstitial pneumonias. The cause of the disease is unknown, and new therapies that stop or reverse disease progression are desperately needed. Recent advances in next-generation sequencing have led to an abundance of freely available, clinically relevant, organ-and-disease-specific, single-cell transcriptomic data, including studies from patients with IPF. We mined data from published IPF data sets and identified gene signatures delineating pro-fibrotic or antifibrotic macrophages and then used the Enrichr platform to identify compounds with the potential to drive the macrophages toward the antifibrotic transcriptotype. We then began testing these compounds in a novel in vitro phenotypic drug screening assay utilising human lung macrophages recovered from whole-lung lavage of patients with silicosis. As predicted by the Enrichr tool, glitazones potently modulated macrophage gene expression towards the antifibrotic phenotype. Next, we assayed a subset of the NatureBank pure compound library and identified the cyclobutane lignan, endiandrin A, which was isolated from the roots of the endemic Australian rainforest plant, Endiandra anthropophagorum , with a similar antifibrotic potential to the glitazones. These methods open new avenues of exploration to find treatments for lung fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE)., Methods: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations., Results: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts., Conclusion: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients., Competing Interests: Conflict of interest: B. Clynick has nothing to disclose. Conflict of interest: T.J. Corte reports grants, personal fees and nonfinancial support from Boehringer Ingelheim, grants and personal fees from Roche, grants from Galapagos, Actelion and Bayer, outside the submitted work. Conflict of interest: H.E. Jo reports other (travel support and lecture fees) from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: I. Stewart has nothing to disclose. Conflict of interest: I.N. Glaspole reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: C. Grainge reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: T.M. Maher reports grants, personal fees and nonfinancial support from UCB, grants and personal fees from GlaxoSmithKline and AstraZeneca, personal fees from Boehringer Ingelheim, Roche, Bayer, Prometic, Samumed, Galapagos, Celgene, Indalo, Pliant, Blade Therapeutics, Respivant, Novartis and Bristol-Myers Squibb, other (stock options) from Apellis, outside the submitted work. Conflict of interest: V. Navaratnam has nothing to disclose. Conflict of interest: R. Hubbard has nothing to disclose. Conflict of interest: P.M.A. Hopkins has nothing to disclose. Conflict of interest: P.N. Reynolds has nothing to disclose. Conflict of interest: S. Chapman reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: C. Zappala has nothing to disclose. Conflict of interest: G.J. Keir has nothing to disclose. Conflict of interest: W.A. Cooper has nothing to disclose. Conflict of interest: A.M. Mahar has nothing to disclose. Conflict of interest: S. Ellis has nothing to disclose. Conflict of interest: N.S. Goh reports grants from the National Health Medical Research Council (NHMRC) (APP1066128, APP114776) and the Centre of Research Excellence in Pulmonary Fibrosis (CRE-PF), Australia (NHMRC GNT116371; 2017-2021), during the conduct of the study; the PROFILE study was funded by the Medical Research Council (G0901226) and GlaxoSmithKline R&D (CRT114316). Conflict of interest: E. De Jong has nothing to disclose. Conflict of interest: L. Cha has nothing to disclose. Conflict of interest: D.B.A. Tan has nothing to disclose. Conflict of interest: L. Leigh has nothing to disclose. Conflict of interest: C. Oldmeadow has nothing to disclose. Conflict of interest: E.H. Walters has nothing to disclose. Conflict of interest: R.G. Jenkins reports other (sponsored research agreements) from AstraZeneca, Biogen and Galecto, outside the submitted work; is on advisory boards for Boehringer Ingelheim, NuMedii, Promedior and Redex; reports lecture fees and consultancy for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Heptares, Pliant and Roche; and is a trustee for Action for Pulmonary Fibrosis. Conflict of interest: Y. Moodley reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the U.S.A., Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients., (© ERS 2014.)