Crystalline silica exposure causes latent biomechanical abnormalities along the cardiopulmonary axis

Rationale Crystalline silica exposure is a major global health burden linked to chronic lung disease and cardiopulmonary morbidity, but early lung-vascular-cardiac abnormalities preceding overt functional decline are poorly defined. Objectives To determine whether a single crystalline silica exposure produces subclinical abnormalities across the integrated axis of cardiopulmonary response (lung[->]pulmonary artery[->]right ventricle) and identify associated sex-dependent physiologic patterns and molecular programs. Methods Male and female mice received a single endotracheal instillation of crystalline silica or vehicle (saline). At 28 days, assessments included voluntary wheel running, diffusion capacity, pulmonary function testing, bronchoalveolar lavage analysis, lung histology and electron microscopy, ex vivo proximal pulmonary artery biomechanics and microstructural second harmonic generation imaging, right ventricular pressure, transthoracic echocardiography, and bulk RNA sequencing of lung and right ventricle. Results Despite recovery of body weight and preserved voluntary exercise, silica-exposed mice demonstrated reduced diffusion capacity, ultrastructural thickening, and disruption of the alveolar-capillary barrier. Bronchoalveolar lavage revealed persistent inflammation with elevated macrophages, lymphocytes, neutrophils, and protein, alongside retained particulate and surfactant-rich debris (silicoproteinosis). Lung mechanics were sex-dependent; females showed a parenchymal-dominant phenotype and males showed increased airway resistance. Elevated pulmonary circulatory pressures caused increased functional stiffness and reduced distensibility of the proximal pulmonary arteries. Right ventricular free wall thickening was noted in females. Lung transcriptomics indicated persistent immune activation and extracellular matrix remodeling, while the right ventricle demonstrated metabolic reprogramming with downregulation of structural and reparative programs. Conclusions A single crystalline silica exposure induces a subclinical, multi-compartment cardiopulmonary phenotype characterized by persistent alveolar-capillary injury, pulmonary vascular stiffening, increased right ventricular afterload, sex-dependent pulmonary mechanics, and divergent organ-level transcriptomic responses.