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Sex-Specific Pathophysiological Signatures in Allometric Dosing-Controlled Bleomycin Acute Lung Injury Model.

Samuel Gillman¹, Alice Ngu², Michael Lush²

¹Department of Genetics, Cell Biology, & Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.

Biorxiv : the Preprint Server for Biology

|April 10, 2026

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This summary is machine-generated.

Body-weight matching in animal models reveals sex differences in acute lung injury (ALI). Males exhibit greater vulnerability, with distinct molecular responses informing potential sex-specific therapies for ALI.

Area of Science:

Pulmonary Medicine
Toxicology
Sex Differences in Disease

Background:

Clinical acute lung injury (ALI) shows similar mortality between sexes, yet women have shorter recovery times.
Preclinical ALI studies report conflicting sex-specific vulnerabilities, possibly due to unrecognized dosing biases.
Intratracheal bleomycin dosing, scaled by body weight, disproportionately affects male rats due to faster body mass growth than lung mass growth.

Purpose of the Study:

To investigate the impact of body-weight matching versus age-matching on sex-specific responses in an ALI rat model.
To identify underlying molecular mechanisms contributing to sex differences in ALI pathogenesis and severity.

Main Methods:

Comparison of age-matched and body-weight-matched Sprague-Dawley rats receiving intratracheal bleomycin.

Keywords:

Alpha 1-antichymotrypsin Bone Morphogenetic Protein Receptors Cytokines Pulmonary inflammation Type II microRNA-672-3p sexual dimorphism

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Functional assessments included plethysmography, lung mechanics, arterial blood gases, and histology.

Mechanistic profiling involved bronchoalveolar lavage fluid analysis, cytokine multiplex assays, and mRNA/miRNA sequencing.

Main Results:

Males in both cohorts exhibited worse hypoxemia and higher respiratory rates compared to females.
Weight-matched males showed increased lung injury markers, including higher BALF protein, IL-1β, and TNF-α.
RNA sequencing revealed distinct gene expression patterns: males upregulated complement-coagulation pathways, while females enriched ECM-remodeling/BMP signaling.

Conclusions:

Body-weight matching is crucial for correcting allometric bias in preclinical ALI sex-difference studies.
Males demonstrate greater vulnerability to ALI, characterized by hypoxemia and specific inflammatory gene activation.
Divergent post-transcriptional regulation, including miR-672-3p suppression in males and preserved IL-10 in females, contributes to functional sex differences and suggests therapeutic targets.