特発性肺線維症

Type II alveolar epithelial cell (AT2) injury has been hypothesized to contribute to pulmonary fibrosis. Cadherin-11 (CDH11) is a mediator of fibrosis and is upregulated on AT2s during lung fibrosis. Herein, the regulation of the AT2 by CDH11 during pulmonary fibrosis was investigated. CDH11 levels were increased in lung samples from patients with idiopathic pulmonary fibrosis (IPF) compared with those from healthy controls. CDH11 expression was inversely correlated with lung function. Cdh11 deficient mice were compared with wild type mice in the intraperitoneal bleomycin model (IP BLM), and the role of the AT2 was investigated using Cdh11 floxed-SPC-Cre mice and in vitro techniques. In the IP BLM model of pulmonary fibrosis, genetic removal of Cdh11 and CDH11 neutralization with monoclonal antibodies reduced pulmonary fibrosis and expression of epithelial injury and mesenchymal markers. Colocalization studies demonstrated that CDH11 was co-expressed with ⍺-SMA on AT2s during fibrosis and inhibition of CDH11 prevented CDH11 co-expression. Furthermore, CDH11 expression was associated with the expression of the AT2 transitional cell marker KRT8 in both in vivo and in vitro studies. Finally, in vitro studies demonstrated that CDH11 engagement, but not N-cadherin engagement, could drive expression of mesenchymal markers in AT2s. Finally, AT2 selective deletion of Cdh11 reduced pulmonary fibrosis in the IP BLM model, confirming that CDH11 regulates the AT2 during the development of lung fibrosis. These data demonstrate that CDH11 is a key regulator of AT2 injury and mesenchymal gene expression during the development of lung fibrosis.

Idiopathic pulmonary fibrosis is a progressive and fatal lung disease in which type 2 immunity has been implicated, yet the upstream signals that sustain pathogenic T helper 2 (Th2) programs and coordinate immune-stromal remodeling remain incompletely defined. We integrated single-cell RNA sequencing from human fibrotic lungs with complementary mechanistic studies in the bleomycin mouse model to test whether CD28 costimulation engages JAK1/STAT6 signaling to drive fibrogenic inflammation. Transcriptomic analyses identified expansion of Th2 cells with elevated CD28 expression and increased STAT6 pathway activity in human IPF and bleomycin-injured mouse lungs, accompanied by transcriptional programs consistent with profibrotic monocyte-derived alveolar macrophages and activated fibroblasts. To establish causality and therapeutic relevance, we perturbed this axis in vivo after injury initiation. Antibody-mediated CD28 blockade, pharmacologic STAT6 inhibition, and genetic STAT6 deficiency each reduced Th2 accumulation and monocyte-derived alveolar macrophages, diminished collagen deposition and histologic fibrosis, and improved lung mechanics. Conversely, agonistic CD28 engagement amplified Th2 and myeloid profibrotic responses, increased collagen accumulation, and worsened pulmonary function. Across species and interventions, changes in Th2-associated signaling tracked with downstream profibrotic myeloid and stromal programs, supporting a coordinated circuit linking adaptive costimulation to fibrotic remodeling. These findings define a CD28-JAK1/STAT6-Th2-monocyte-derived alveolar macrophage pathway as a mechanistic driver of pulmonary fibrosis and nominate CD28 and STAT6 as actionable immunologic targets that could complement existing antifibrotic therapies.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) of unclear etiology. Dupilumab, a humanized monoclonal antibody binding to interleukin-4 receptor alpha (IL-4Rα), suppresses both IL-4 and IL-13 signaling pathways. However, the therapeutic potential in IPF is unclear. This research aimed to evaluate the antifibrotic efficacy of dupilumab and illustrate the underlying mechanisms. METHODS: The antifibrotic efficacy of dupilumab was assessed both in vitro and in vivo. In vitro, a fibroblast activation model and a macrophage-fibroblast co-culture model were established. In vivo, pulmonary fibrosis was induced in C57BL/6 mice by intratracheal bleomycin injection. Lung function, micro-computed tomography (micro-CT), histopathology, inflammatory responses, and fibrosis-related signaling pathways were assessed. RESULTS: Dupilumab significantly suppressed TGF-β1-induced fibroblast activation. In the macrophage-fibroblast coculture system, dupilumab inhibited the profibrotic phenotype of IL-4/IL-13-stimulated macrophages, as well as macrophage-induced myofibroblast activation. In bleomycin-challenged mice, dupilumab improved pulmonary function, alleviated radiographic and histopathological fibrosis, reduced inflammatory cell counts and inflammatory cytokine levels in bronchoalveolar lavage fluid. Mechanistically, dupilumab suppressed activation of both the TGF-β1/Smad and JAK/STAT pathways in fibrotic lung tissues. CONCLUSIONS: Dupilumab attenuates pulmonary fibrosis by disrupting profibrotic macrophage-fibroblast crosstalk and suppressing fibroblast activation. In preclinical models, dupilumab mitigated BLM-induced pulmonary inflammation and early-stage fibrosis in mice and inhibited the TGF-β1-Smad and JAK-STAT signal transduction cascades. These findings identify IL-4Rα-mediated signaling as a promising intervention point in pulmonary fibrosis and support further investigation of dupilumab as a candidate therapy for fibrotic lung diseases.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease characterized by usual interstitial pneumonia, relentless decline in lung function and incomplete disease modification by available antifibrotic therapies. Beyond canonical profibrotic pathways, accumulating evidence identifies aberrant glutamine metabolism as a convergent metabolic feature of IPF pathogenesis. In structural cells, glutaminolysis fuels myofibroblast activation, de novo glycine and proline synthesis for collagen, whereas epithelial glutamine utilization may support antioxidant defence, mitochondrial adaptation and repair. In immune cells, glutamine shapes macrophage and T-cell polarization and may contribute to an inflammatory, profibrotic microenvironment. Glutamine-derived intermediates intersect with mTOR/AMPK and TGF-β/Smad signalling and act as cofactors for epigenetic regulators, thereby stabilizing apoptosis-resistant, profibrotic transcriptional programmes. Experimental models and human studies further demonstrate upregulation of glutamine transporters and glutaminase 1 (GLS1) in fibrotic lungs, protection from bleomycin-induced fibrosis after genetic or pharmacologic GLS1 inhibition, and a genetic association between lower circulating glutamine and increased IPF risk. Importantly, the effects of glutamine metabolism are context- and cell type-dependent: epithelial and immune glutamine utilization may support repair, barrier integrity and host defence, whereas excessive fibroblast-directed glutaminolysis promotes matrix accumulation. Building on these observations, this review synthesizes current knowledge on cell type-relevant glutamine metabolism in lung fibrosis, distinguishes direct lung-fibrosis evidence from extrapolated mechanistic evidence, delineates its integration with fibrogenic signalling, oxidative stress, mitochondrial stress and immunometabolism, and critically evaluates the therapeutic potential and caveats of targeting glutamine uptake, catabolism and nutrient-sensing pathways as adjuncts to existing antifibrotic regimens.