bioRxiv : the preprint server for biology · 2026
Myeloid HIF-1α Sustains Hypoxic Fibrotic Fronts and Drives Pulmonary Fibrosis.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Wei Yuanyi, Bailey Christopher, Zhang Peng, Herazo-Maya Jose, Karampitsakos Theodoros, Pescrille Joseph, Diaz-Mendez Felisa, Lee Daniel, Samokhin Andriy, Liu Yan, Drake Wonder, Wang Yin
Аннотация
RATIONALE: Progressive fibrosing interstitial lung disease features "advancing fronts" where new matrix is deposited, but the signals sustaining these propagating niches remain incompletely defined.
OBJECTIVES: To determine the spatial and temporal compartments in which HIF-1α operates during fibrotic progression and to test whether myeloid HIF-1α is a tractable driver of lesion propagation.
METHODS: We integrated human IPF datasets, clinical severity profiling, sarcoidosis peripheral blood immune phenotyping, multiplex immunofluorescence and spatial mapping in human lung tissue, single-cell transcriptomic analyses, and temporally staged bleomycin lung injury with genetic and lung-directed therapeutic perturbations.
MEASUREMENTS AND MAIN RESULTS: In the Lung Genome Research Consortium cohort, HIF1A expression was increased in IPF lungs and correlated with higher GAP scores. In sarcoidosis, circulating monocytes from patients with progressive disease exhibited increased HIF-1α compared with those with resolving disease. In IPF lungs, nuclear HIF-1α localized predominantly to CD68⁺ macrophages and PDGFRα⁺ fibroblasts concentrated within collagen-rich, αSMA⁺ advancing fronts, and single-cell analyses demonstrated enrichment of HIF-1α-linked transcriptional programs consistent with macrophage-fibroblast crosstalk (including pro-fibrotic growth factors, chemokines, and matrix-regulatory pathways). In bleomycin-induced fibrosis, HIF-1α activity emerged first in macrophages and subsequently in fibroblasts within pimonidazole-marked hypoxic rims bordering nascent αSMA⁺ foci. Myeloid-specific Hif1a deletion reduced front-associated macrophage persistence, attenuated fibroblast activation, and decreased collagen deposition. Two lung-directed strategies, inhaled liposomal echinomycin and inhaled shHif1a lipid nanoparticles, phenocopied these effects, demonstrating therapeutic tractability.
CONCLUSIONS: These findings define a hypoxic front-zone niche in which myeloid HIF-1α sustains macrophage persistence and promotes fibroblast activation and matrix remodeling. By linking spatial compartmentalization to causal genetics and lung-directed intervention, our work identifies myeloid HIF-1α as a mechanism-anchored, locally targetable driver of fibrotic lesion propagation.
OBJECTIVES: To determine the spatial and temporal compartments in which HIF-1α operates during fibrotic progression and to test whether myeloid HIF-1α is a tractable driver of lesion propagation.
METHODS: We integrated human IPF datasets, clinical severity profiling, sarcoidosis peripheral blood immune phenotyping, multiplex immunofluorescence and spatial mapping in human lung tissue, single-cell transcriptomic analyses, and temporally staged bleomycin lung injury with genetic and lung-directed therapeutic perturbations.
MEASUREMENTS AND MAIN RESULTS: In the Lung Genome Research Consortium cohort, HIF1A expression was increased in IPF lungs and correlated with higher GAP scores. In sarcoidosis, circulating monocytes from patients with progressive disease exhibited increased HIF-1α compared with those with resolving disease. In IPF lungs, nuclear HIF-1α localized predominantly to CD68⁺ macrophages and PDGFRα⁺ fibroblasts concentrated within collagen-rich, αSMA⁺ advancing fronts, and single-cell analyses demonstrated enrichment of HIF-1α-linked transcriptional programs consistent with macrophage-fibroblast crosstalk (including pro-fibrotic growth factors, chemokines, and matrix-regulatory pathways). In bleomycin-induced fibrosis, HIF-1α activity emerged first in macrophages and subsequently in fibroblasts within pimonidazole-marked hypoxic rims bordering nascent αSMA⁺ foci. Myeloid-specific Hif1a deletion reduced front-associated macrophage persistence, attenuated fibroblast activation, and decreased collagen deposition. Two lung-directed strategies, inhaled liposomal echinomycin and inhaled shHif1a lipid nanoparticles, phenocopied these effects, demonstrating therapeutic tractability.
CONCLUSIONS: These findings define a hypoxic front-zone niche in which myeloid HIF-1α sustains macrophage persistence and promotes fibroblast activation and matrix remodeling. By linking spatial compartmentalization to causal genetics and lung-directed intervention, our work identifies myeloid HIF-1α as a mechanism-anchored, locally targetable driver of fibrotic lesion propagation.