Biology subjects

Zuluaga, J. D.

Publications and source records attributed to Zuluaga, J. D..

3 recordsLinked to original sources

bioRxiv2026

Early Pulmonary Fibrosis is Defined by Niche- and Cell-Specific Molecular Programs

RationalePreclinical familial pulmonary fibrosis (FPF) represents an early stage of fibrotic lung disease, yet the compartment- and cell-specific molecular programs preceding fibrosis remain poorly understood. ObjectiveTo define spatially organized molecular signatures associated with preclinical FPF and identify tissue-informed circulating biomarkers linked to early fibrotic remodeling. MethodsWe performed integrated multi-omic profiling of histologically preserved and remodeled lung regions from subjects with preclinical FPF, Idiopathic Pulmonary Fibrosis (IPF), and controls using spatial transcriptomics, single-nucleus RNA sequencing (snRNAseq), and blood proteomics. Differential expression and pathway enrichment analyses were performed across spatial compartments and epithelial cell states. ResultsHistologically preserved lung regions in preclinical FPF demonstrated transcriptional abnormalities including stress-response, ciliary, and extracellular matrix-associated programs despite minimal architectural distortion. Spatial analyses identified alterations in alveolar niche molecular programs accompanied by increasing profibrotic signaling across preserved and tissue remodeled lung compartments. Compared with advanced IPF, preclinical FPF retained epithelial repair and surfactant-associated signatures. Integration with snRNAseq demonstrated enrichment of alveolar and airway epithelial cell dysregulated states associated with transitional phenotypes previously implicated in IPF. Compartment- and epithelial-associated transcriptional signatures identified in lung tissue were partially represented in the peripheral blood. ConclusionPreclinical FPF is characterized by compartment- and cell-specific molecular programs that precede established fibrosis. We identified distinct alveolar, airway, and vascular molecular signatures and epithelial remodeling states represented in the peripheral blood. These findings provide an initial framework for molecular classification of early stages of pulmonary fibrosis and support future studies evaluating minimally invasive approaches for disease stratification and precision therapeutics. At a Glance Commentary Scientific Knowledge on the SubjectThe molecular events preceding a diagnosis of pulmonary fibrosis remain poorly understood. Most mechanistic studies in Idiopathic Pulmonary Fibrosis (IPF) have relied on end-stage explanted lungs, limiting insight into the compartment- and cell-specific molecular programs associated with early stages of pulmonary fibrosis. What this study adds to the fieldUsing integrated spatial transcriptomics, single-cell sequencing, and peripheral blood proteomic profiling, we demonstrate that preclinical familial pulmonary fibrosis (FPF) is characterized by compartment- and cell-specific molecular programs that precede clinically detectable fibrosis. Spatial analyses identified distinct alveolar, airway, and vascular molecular signatures, while single cell analysis confirmed the presence of epithelial dysregulated states. These signatures are partially represented in the peripheral blood. Our findings provide an initial framework for biologically informed classification of early stages of pulmonary fibrosis and future minimally invasive approaches for disease stratification.

genomics↗

bioRxiv2025

Single cell transcriptomics in a treatment-segregated cohort exposes a STAT3-regulated therapeutic gap in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disease of unknown etiology. Since approved IPF drugs only slow disease progression, novel therapeutics are required that improve clinical outcomes. Here we report a single cell lung RNA-Seq and gene regulatory network analysis of the largest IPF cohort assembled to date. Segregating this cohort based on status of treatment with approved first-generation IPF antifibrotics (untreated, nintedanib- and pirfenidone-treated), we describe for the first time the transcriptional landscape of untreated IPF across 40 lung cell types, and the elements of this program that are impacted by these antifibrotics. On average, nearly 60% of the untreated IPF-dysregulated transcriptome is refractory to treatment with these drugs, a transcriptional deficit we refer to as the IPF therapeutic gap. Gene regulatory network analysis indicated a dominant functional footprint for the transcription factor STAT3 in both untreated IPF and the IPF therapeutic gap. Validating our analysis in a translational precision cut lung slice platform that recapitulates IPF explants, pharmacological inhibition of STAT3 reduced the IPF therapeutic gap in numerous lung cell types. Finally, we resolved a STAT3-anchored master regulatory network comprising numerous profibrotic transcription factors in IPF alveolar fibroblasts, a critical fibrotic lineage. Our study represents a comprehensive resource for translational lung fibrosis research and introduces a strategy for drug discovery that is adaptable to human disease more broadly.

cell biology↗

bioRxiv2025

Warming up to a new coat: moulting king penguins exhibit hyperthermia and increased peripheral heat loss

Penguins are among the most specialized thermoregulators on the planet, however, the same adaptations that maximize heat retention underwater likely hinder heat dissipation on land, possibly creating dangerous thermoregulatory challenges when encountering warming terrestrial habitats. Penguins are subject to strictly terrestrial phases, such as moulting, when metabolic heat production, insulation, and energetic constraints are heightened. We assessed thermoregulation in moulting captive king penguins (Aptenodytes patagonicus) using simultaneous measurements of core and surface temperatures to test two hypotheses. Under the thermal challenge hypothesis, an initial rise in heat dissipation effort (i.e., increased peripheral vasomotion) followed by a rise in core temperature would indicate failure to prevent hyperthermia. Under the warm-up hypothesis, an initial rise of core temperature concomitant or followed by an increase of peripheral vasomotion would indicate regulated hyperthermia, possibly to accelerate feather development. Core and surface temperatures increased drastically but concomitantly during moult, providing tentative support for the warm-up hypothesis. Moulting penguins did not pant, suggesting that peripheral heat dissipation was sufficient to regulate moulting-induced hyperthermia. Core and subcutaneous temperatures in wild individuals resembled patterns measured in captivity, despite lower heat load and additional options for behavioural thermoregulation. These results indicate that hyperthermia is prevalent in moulting king penguins, and documenting the timing of temperature changes provides novel insights for the moulting physiology of penguins. Because moulting-induced hyperthermia may contribute to heat load, we caution that moulting may increase the susceptibility of wild penguins to heat stress, especially as regions near the poles warm at a disproportionately rapid rate.

physiology↗