Dysregulated alveolar epithelial maintenance in Hermansky-Pudlak syndrome pulmonary fibrosis
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PROVIDER: PRJNA986574 | ENA |
REPOSITORIES: ENA
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Project description:Hermansky-Pudlak syndrome (HPS) is a genetic disorder of intracellular endosomal trafficking defects associated with pulmonary fibrosis. Double mutant HPS1/2 mice exhibit spontaneous fibrosis and single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity. To identify mechanisms of AT2 cell dysfunction contributing to fibrosis in HPS, we examined lungs from aged HPS1/2 mice and observed regions of AT2 cell loss adjacent to areas of marked AT2 cell hyperplasia as compared to wild type (WT). Overall, there was accelerated loss of AT2 cells in HPS1/2, HPS1, and HPS2 mice with aging based on immunohistochemistry and lineage tracing studies. Lung organoids generated with HPS2 AT2 cells with WT fibroblasts were smaller in size and displayed significantly decreased colony forming efficiency compared to organoids with WT AT2 cells. Utilizing an H1N1 PR8 influenza model to examine AT2 cell regeneration after injury, there was a significant decrease in the percentage of proliferating AT2 cells in HPS1 and HPS2 mice compared to WT mice. RNA sequencing of AT2 cells isolated from unchallenged mice demonstrated upregulation of genes associated with proliferation and cellular senescence in HPS AT2 cells. Collectively, AT2 cells in HPS mice exhibit dysregulated proliferation with transcriptomic features suggesting subpopulations of senescent and hyperproliferative cells. Dysregulated maintenance of the alveolar epithelium with accelerated senescence and aberrant proliferation of AT2 cells appears to be a shared pathway underlying HPS and other sporadic and genetic forms of pulmonary fibrosis.
2025-01-08 | GSE235628 | GEO
Project description:Introduction of Hermansky-Pudlak Syndrome-associated mutations with CRISPR/Cas9 genome editing, allows for disease modeling in 3D cultures of hPSC-derived lung organoids.
2019-06-25 | GSE121999 | GEO
Project description:Hermansky-Pudlak syndrome (HPS), particularly in types 1 and 4, is characterized by progressive pulmonary fibrosis, a major cause of morbidity and mortality. However, the precise mechanisms driving pulmonary fibrosis in HPS are not fully elucidated. Our previous studies have suggested that CHI3L1-driven fibroproliferation may be a significant factor in HPS-associated fibrosis. This study aimed to explore the role of CHI3L1-CRTH2 interaction on ILC2s and explored the potential contribution of ILC2-fibroblast crosstalk in the development of pulmonary fibrosis in HPS. We identified ILC2s in lung tissues from idiopathic pulmonary fibrosis (IPF) and HPS patients. Our findings suggest that ILC2s may directly stimulate the proliferation and differentiation of primary lung fibroblasts partially through Areg-EGFR-dependent mechanisms. Additionally, specific overexpression of CHI3L1 in the ILC2 population using the IL-7Rcre driver, which was associated with increased fibroproliferation, indicates that ILC2-mediated, CRTH2-dependent mechanisms might contribute to optimal CHI3L1-induced fibroproliferative repair in HPS-associated pulmonary fibrosis.
2024-10-11 | GSE278788 | GEO
Project description:Type 2 innate immunity promotes the development of pulmonary fibrosis in Hermansky-Pudlak syndrome
| PRJNA1168925 | ENA
Project description:Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.
| S-EPMC5466158 | biostudies-literature
Project description:RationaleIndividuals with Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, develop an accelerated form of progressive fibrotic lung disease. The etiology of pulmonary fibrosis associated with HPS-1 is unknown.ObjectivesTo investigate the potential pathogenesis of pulmonary fibrosis in HPS-1, lung cells and proteins from individuals with HPS-1 were studied.MethodsForty-one subjects with HPS-1 with and without pulmonary fibrosis were evaluated with pulmonary function tests, high-resolution computed tomography scan, and bronchoscopy. Bronchoalveolar lavage cells and analytes were analyzed.Measurements and main resultsConcentrations of total bronchoalveolar lavage cells and alveolar macrophages were significantly higher in epithelial lining fluid from subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers. Concentrations of cytokines and chemokines (i.e., monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and granulocyte-macrophage colony-stimulating factor) in alveolar epithelial lining fluid were significantly higher in subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers (P < 0.001). In vitro, HPS-1 pulmonary fibrosis alveolar macrophages, which did not express HPS1 mRNA, secreted significantly higher concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and regulated upon activation, normal T cell expressed and secreted (RANTES) protein compared with normal cells (P = 0.001, P = 0.014, and P = 0.011, respectively). Pirfenidone suppressed HPS-1 alveolar macrophage cytokine and chemokine secretion in vitro in a dose-dependent manner.ConclusionsIn HPS-1, alveolar inflammation predominantly involves macrophages and is associated with high lung concentrations of cytokines and chemokines. HPS-1 alveolar macrophages provide a model system in which to study the pathogenesis and treatment of HPS pulmonary fibrosis.
| S-EPMC2784416 | biostudies-literature
Project description:Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells
| PRJNA745557 | ENA
Project description:Mendelian diseases that present with immune-mediated disorders can provide insights into the molecular mechanisms that drive inflammation. Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking involving the BLOC-3 complex. The presence of inflammatory complications such as Crohn’s disease-like inflammation and lung fibrosis in these patients remains enigmatic. Using mass cytometry we observe an augmented inflammatory monocyte compartment in HPS1 patient peripheral blood that may be associated with a TNF - and IL-1α-dominated cytokine dysregulation. HPS1 patient monocyte-derived macrophages express an inflammatory TNF-OSM mRNA gene signature and changes in lipid metabolism. Using stimulation experiments and lysosomal proteomics we show that defective lipid metabolism drives RAB32-dependent mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic circuit translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. We reveal that a pathogenic lipid-mTOR signaling circuit acts as a metabolic checkpoint for defective anti-microbial activity. This mechanism may be relevant to the complex pathology of HPS1 patients featuring macrophage lipid accumulation, granuloma formation, defective anti-microbial activity and tissue inflammation. Lastly, this circuit may be present in a wider group of disorders with defective lipid metabolism and cholesterol accumulation.
2022-11-02 | PXD024435 | Pride
Project description:RationaleHermansky-Pudlak syndrome (HPS) is a family of recessive disorders of intracellular trafficking defects that are associated with highly penetrant pulmonary fibrosis. Naturally occurring HPS mice reliably model important features of the human disease, including constitutive alveolar macrophage activation and susceptibility to profibrotic stimuli.ObjectivesTo decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS.MethodsWe used five different HPS and Chediak-Higashi mouse models to evaluate genotype-specific fibrotic susceptibility. To determine whether intrinsic defects in HPS alveolar macrophages cause fibrotic susceptibility, we generated bone marrow chimeras in HPS and wild-type mice. To directly test the contribution of the pulmonary epithelium, we developed a transgenic model with epithelial-specific correction of the HPS2 defect in an HPS mouse model.Measurements and main resultsBone marrow transplantation experiments demonstrated that both constitutive alveolar macrophage activation and increased susceptibility to bleomycin-induced fibrosis were conferred by the genotype of the lung epithelium, rather than that of the bone marrow-derived, cellular compartment. Furthermore, transgenic epithelial-specific correction of the HPS defect significantly attenuated bleomycin-induced alveolar epithelial apoptosis, fibrotic susceptibility, and macrophage activation. Type II cell apoptosis was genotype specific, caspase dependent, and correlated with the degree of fibrotic susceptibility.ConclusionsWe conclude that pulmonary fibrosis in naturally occurring HPS mice is driven by intracellular trafficking defects that lower the threshold for pulmonary epithelial apoptosis. Our findings demonstrate a pivotal role for the alveolar epithelium in the maintenance of alveolar homeostasis and regulation of alveolar macrophage activation.
| S-EPMC3530211 | biostudies-literature
Project description:Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPS cells (NaPi2Bhigh cells)
| PRJNA745560 | ENA