Biology subjects

Noble, P.

Publications and source records attributed to Noble, P..

5 recordsLinked to original sources

bioRxiv2025

Phosphatidylcholine Metabolism Controls Alveolar Progenitor Renewal and Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease marked by alveolar type 2 (AT2) stem cell dysfunction and excessive matrix deposition, with no effective treatments. Recent advances have recognized that AT2 cells act as stem cells, in addition to their role in the production of pulmonary surfactants in the distal alveolar space. We and others have reported a failure of AT2 regeneration and a loss of AT2 cells in IPF. We recently further reported that there is a defect in lipid metabolism in IPF AT2 cells and we discovered a selective loss of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in AT2 cells from IPF, as well as in AT2 cells from bleomycin-injured mice. Pharmacological and genetic experiments confirm that LPCAT1 is required for AT2 cell renewal in 3D organoid assays. AT2 cell-specific Lpcat1 deletion resulted in reduced AT2 renewal, spontaneous lung fibrosis, and heightened susceptibility to bleomycin-induced fibrosis in mice in vivo. Expression-based high-content drug screening with an LPCAT1 knock-in cell line identified several drug families that upregulated LPCAT1 expression. We further confirmed that anti-malarial artesunate and PLA2 inhibitor ONO-RS-082 increased LPCAT1 mRNA expression, promoted AT2 renewal, and attenuated bleomycin-induced lung fibrosis in mice in vivo. Our findings establish LPCAT1 as a critical regulator of AT2 renewal and lipid metabolism in IPF, suggesting that reactivation of LPCAT1 could offer a novel therapeutic strategy for restoring alveolar progenitor function and mitigating lung fibrosis.

cell biology↗

bioRxiv2025

Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell homeostasis in idiopathic pulmonary fibrosis and reverses pulmonary fibrosis in mice

Alveolar type II (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central regulator of cellular energy metabolism. We have reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2s. In this study, we identified that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2s. NAMPT deficiency impairs AT2 renewal and enhances lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, induction of pathological transitional gene expression and impaired regenerative capacity to generate alveolar type I (AT1) cell required for gas exchange. Mice with deletion of Nampt in AT2s showed severely impaired AT2 renewal and increased susceptibility to bleomycin lung injury and spontaneous fibrois. Activation of NAMPT by small molecule activators promoted AT2 renewal, restored homeostasis, and reversed lung fibrosis. NAMPT activation could be a therapeutic strategy for restoring AT2 progenitor function and halting or reversing progressive pulmonary fibrosis.

cell biology↗

bioRxiv2020

Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease and aging has been identified as a risk factor to the disease. Alveolar type II cells (AEC2s) function as progenitor cells in the lung. Growing evidences indicate that IPF results from repeating AEC2 injury and inadequate epithelial repair. We previously reported that there was a significant loss of alveolar progenitors in the lungs of patients with IPF. In our current study, we performed single cell RNA-seq of epithelial cells from lungs of patients with IPF and healthy donors as well as epithelial cells from old and young mouse lungs with bleomycin injury. We identified a defect of zinc metabolism of AEC2s from IPF lungs and bleomycin-injured old mouse lungs. We further discovered that a specific zinc transporter ZIP8 was down regulated in IPF AEC2s and AEC2s from aged mice. Loss of ZIP8 expression is associated with impaired AEC2 renewal through sirtuin signaling in aging and IPF. Targeted deletion of Zip8 in murine AEC2 compartment led to reduced AEC2 renewal capacity, impaired AEC2 recovery, and worsened lung fibrosis after bleomycin injury. In summary, we have identified novel metabolic defects of AEC2s during aging and in IPF which contribute to the pathogenesis of lung fibrosis. Therapeutic strategies to restore critical components of these metabolic programs could improve AEC2 progenitor activity and mitigate ongoing fibrogenesis. In BriefLiang et al. performed single cell RNA-seq (scRNA-seq) of epithelial cells in IPF and in mice and discovered a zinc metabolic defect of alveolar progenitor cells (AEC2) in IPF and injured old mice characterized by down-regulation of a specific zinc transporter ZIP8. Manipulation of ZIP8 and zinc in 3D organoid culture of AEC2 in vitro and targeted deletion of Zip8 in AEC2s in vivo demonsrated a role of ZIP8 in promoting AEC2 progenitor function. HighlightsO_LIScRNA-seq revealed dysregulation of zinc metabolism in AEC2s and decreased stem cell signaling in IPF C_LIO_LIReduced SLC39A8 and related gene expression of IPF AEC2s and aged mouse AEC2s C_LIO_LIZIP8-dependent zinc metabolism is required for AEC2 renewal C_LIO_LITargeted deletion of Slc39a8 impaired AEC2 renewal and promoted lung fibrosis C_LI

cell biology↗

bioRxiv2020

Single cell reconstruction of human basal cell diversity in normal and IPF lung.

RationaleDeclining lung function in patients with interstitial lung disease is accompanied by epithelial remodeling and progressive scarring of the gas-exchange region. There is a need to better understand the contribution of basal cell hyperplasia and associated mucosecretory dysfunction to the development of idiopathic pulmonary fibrosis (IPF). ObjectivesWe sought to decipher the transcriptome of freshly isolated epithelial cells from normal and IPF lung to discern disease-dependent changes within basal stem cells. MethodsSingle cell RNA sequencing was used to map epithelial cell types of the normal and IPF human airway. Organoid and ALI cultures were used to investigate functional properties of basal cell subtypes. Measurements and Main ResultsWe found that basal cells included multipotent and secretory primed subsets in control adult lung tissue. Secretory primed basal cells include an overlapping molecular signature with basal cells obtained from distal lung tissue of IPF lungs. We confirmed that NOTCH2 maintains undifferentiated basal cells and restrict basal-to-ciliated differentiation, and present evidence that NOTCH3 functions to restrain secretory differentiation. ConclusionsBasal cells are dynamically regulated in disease and are specifically biased towards expansion of the secretory primed basal cell subset in idiopathic pulmonary fibrosis. Modulation of basal cell plasticity may represent a relevant target for therapeutic intervention in IPF.

cell biology↗

bioRxiv2018

IL-11 is a therapeutic target in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) remains a progressive disease despite best medical management. We previously identified IL-11 as a critical factor for cardiovascular fibrosis and examine here its role in pulmonary fibrosis. IL-11 is consistently upregulated in IPF genomic datasets, which we confirmed by histology. Pulmonary fibroblasts stimulated with IL-11 transform into invasive myofibroblasts whereas fibroblasts from Il11ra deleted mice did not respond to pro-fibrotic stimuli. In the mouse, injection of recombinant Il-11 or fibroblast-specific expression of Il-11 caused pulmonary fibrosis. We then generated a neutralising IL-11 binding antibody that blocks lung fibroblast activation across species. In a mouse model of IPF, anti-IL-11 therapy attenuated lung fibrosis and specifically blocked Erk activation. These data prioritise IL-11 as an accessible drug target in IPF.\n\nOne Sentence SummaryNon-canonical IL-11 signalling is a central hallmark of idiopathic pulmonary fibrosis and represents a novel target for antibody therapies.

molecular biology↗