Arnaud A. Mailleux

Pulmonary fibrosis is increasingly viewed as a lung-centered disease influenced by systemic metabolic and inflammatory context. Adipose tissue, through its endocrine, paracrine, and immunometabolic functions, may act as a systemic modifier rather than a primary initiator of fibrotic remodeling. Epidemiologic and imaging studies link visceral adiposity, body composition, and adipose-related mediators such as leptin and IL-6 with subclinical interstitial abnormalities and outcomes in fibrotic ILD, while genetic and clinical data support a context-dependent protective role for adiponectin signaling. Mechanistic evidence suggests that adipose dysfunction may influence fibrotic remodeling through adipokine imbalance, inflammasome activation, perivascular inflammation, profibrotic macrophage polarization, epithelial maladaptation, cellular senescence, and fibroblast metabolic reprogramming. These pathways may converge to sustain myofibroblast activation and extracellular matrix deposition. Clinically, adipose dysfunction overlaps with common ILD comorbidities and may inform metabolic phenotyping, biomarker development, and patient stratification. Therapeutic implications remain investigational, with the strongest rationale supporting metabolic reprogramming strategies and biomarker-enriched studies rather than routine adipose-targeted therapy. Overall, the adipose–lung axis provides a framework for integrating systemic metabolic biology into the pathogenesis and clinical management of fibrotic ILD.

Idiopathic pulmonary fibrosis (IPF) is a rare and fatal lung disease caused by progressive damage to alveolar epithelial cells, leading to abnormal activation of mesenchymal cells. The PRRX1 transcription factor (TF) has been found to be reactivated in IPF and was previously identified as a key mesenchymal TF in pulmonary fibrosis. In this study, we utilized the Prrx1:CreERT2; Rosa26iTomato murine transgenic line to further characterize the Prrx1-positive cell lineage in healthy and fibrotic lungs. The Prrx1 limb enhancer (Prrx1enh) was undetectable by immunohistochemistry in uninjured lung tissue. However, during the fibrotic phase in the bleomycin model of pulmonary fibrosis, Prrx1enh became activated, marking a population of cells that differentiated into mesenchymal progeny. To investigate further, we conducted reprogramming of these subpopulations after conditional and inducible Prrx1 loss of function. Prrx1 loss in these cells led to worsened fibrosis, indicating that this specific cell population has antifibrotic properties. Our findings reveal a previously unrecognized subpopulation of Prrx1-positive mesenchymal cells that are activated during fibrogenesis. These cells could serve as targets for future therapies aimed at mitigating fibrotic progression in IPF.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal disease with limited therapeutic options. FGF21 (fibroblast growth factor 21), an endocrine fibroblast growth factor that acts through the FGFR1 (fibroblast growth factor receptor 1)/KLB (β-Klotho) pathway, mitigates liver fibrosis. Objectives: We hypothesized that FGF21 could exert antifibrotic properties in the lung. Methods: The concentrations of FGF21 and KLB in the plasma of patients with IPF and control subjects were assessed. Pulmonary fibrosis development was assessed in Fgf21-deficient mice compared with wild-type littermates, at Day 14 (D14) after the intratracheal injection of bleomycin. We determined the effect of repeated subcutaneous injections of a PEGylated FGF21 analog at D7, D10, D14, and D17 after bleomycin on the development of pulmonary fibrosis. Mice were killed at D21. The effects of FGF21, alone or with KLB, on apoptosis in murine lung epithelial 15 cells and on the phenotype of human lung fibroblasts were assessed in vitro. Measurements and Main Results: In the plasma of patients with IPF, FGF21 concentrations were increased, while KLB concentrations were decreased. Fgf21-deficient mice showed increased sensitivity to bleomycin in comparison with their wild-type littermates. Treatment with PEGylated FGF21 mitigated lung fibrogenesis, as evidenced by a lower injury score and decreased fibrosis markers and profibrotic mediator expression compared with the control group receiving the diluent. In murine lung epithelial 15 cells, stimulation with FGF21 and KLB inhibited apoptosis, through the decrease of BAX and BIM. Fibroblastic phenotype remained unaltered. Conclusions: Our data indicate a possible antifibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cell apoptosis.

FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.

Early career members of Assembly 3 (Basic and Translational Sciences) of the European Respiratory Society (ERS) summarise the key messages discussed during six selected sessions that took place at the ERS International Congress 2023 in Milan, Italy. Aligned with the theme of the congress, the first session covered is “Micro- and macro-environments and respiratory health”, which is followed by a summary of the “Scientific year in review” session. Next, recent advances in experimental methodologies and new technologies are discussed from the “Tissue modelling and remodelling” session and a summary provided of the translational science session, “What did you always want to know about omics analyses for clinical practice?”, which was organised as part of the ERS Translational Science initiative's aims. The “Lost in translation: new insights into cell-to-cell crosstalk in lung disease” session highlighted how next-generation sequencing can be integrated with laboratory methods, and a final summary of studies is presented from the “From the transcriptome landscape to innovative preclinical models in lung diseases” session, which links the transcriptome landscape with innovative preclinical models. The wide range of topics covered in the selected sessions and the high quality of the research discussed demonstrate the strength of the basic and translational science being presented at the international respiratory conference organised by the ERS.

Tweetable abstract Integrated multi-omic single cell analyses in IPF lungs highlights TWIST1 as a critical transcriptional regulator for myofibroblastshttps://bit.ly/3qBjh0S

Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR-dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis.

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease with a poor prognosis. Chronic microinjuries, mainly caused by environmental factors to an aging alveolar epithelium, would lead to the aberrant differentiation and accumulation of aberrant mesenchymal cells with a contractile phenotype, known as fibrosis-associated myofibroblasts, which trigger abnormal extracellular matrix accumulation and fibrosis. The origin of those pathological myofibroblasts in pulmonary fibrosis is not fully understood to date. Lineage tracing methods using mouse models have opened new avenues for studying cell fate in a pathological context. This review aims to present a nonexhaustive list of different potential sources of those harmful myofibroblasts during lung fibrosis, based on these in vivo approaches, and considering the normal and fibrotic lung cellular atlas recently established by single-cell RNA sequencing.