2026-06-14T13:28:19Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/273832026-04-01T00:15:52Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Jimenez-Garcia, Lidia author Pérez-Montero, Andrea author Herranz, Sandra author Luque, Alfonso author Tarín, Carlos author Castillo, Diego author Lopez-Vilaro, Laura author Mariñas-Pardo, Luis author McCarthy, Cormac author Acebo, Paloma author Hortelano, Sonsoles author 2026-02-05 The alternative reading frame (ARF) protein, encoded by the CDKN2A locus, is well-recognized for its role in tumor suppression. Emerging evidence has highlighted ARF as a critical regulator of innate immunity and inflammation, with links to increased susceptibility to cardio-metabolic diseases. This study investigates the role of ARF in lung homeostasis and reveals that its deficiency in mice affects lipid metabolism and leads to pulmonary abnormalities resembling pulmonary alveolar proteinosis (PAP). ARF-deficient mice exhibited abnormal surfactant clearance, characterized by lipid and protein accumulation in the alveoli, foamy alveolar macrophages (AMs) with enlarged and vacuolated morphology, and increased bronchoalveolar lavage fluid (BALF) turbidity. These changes were linked to disrupted surfactant homeostasis resulting from an imbalance between increased lipid uptake (via upregulation of scavenger receptors such as SR-A1 and CD36) and impaired lipid efflux, evidenced by reduced expression of the cholesterol transporter SR-BI. These mice also display reduced AMs numbers, increased eosinophil and neutrophil infiltration, consistent with secondary PAP. Additionally, a distinctive chemokine and cytokine profile (elevated Ccl12, Ccl2, Cxcl1, and IL10) was observed, which may be associated with type 2 immune responses and alternative AMs polarization. Interestingly, ARF deficiency also appears to compromise AMs maintenance through effects on self-renewal and survival. Pulmonary function tests revealed increased tissue elastance and damping, suggesting early-stage lung stiffness. Collectively, these findings highlight the essential role of ARF in lung homeostasis and lipid regulation, providing insights into its potential involvement in PAP pathogenesis. Lidia Jiménez-Garcia, Andrea Pérez-Montero, Sandra Herranz, Alfonso Luque, Carlos Tarín, Diego Castillo, Laura Lopez-Vilaro, Luis Mariñas-Pardo, Cormac McCarthy, Paloma Acebo, Sonsoles Hortelano, p19ARF Deficiency Disrupts Lung and Lipid Homeostasis Resembling the Human Alveolar Proteinosis, American Journal of Respiratory Cell and Molecular Biology, 2026;, aanag003, https://doi.org/10.1093/ajrcmb/aanag003. 10.1093/ajrcmb/aanag003 American Journal of Respiratory Cell and Molecular Biology 41738246 https://hdl.handle.net/20.500.12105/27383 Alveolar macrophages Inflammatory profile Lipids p19ARF Pulmonary alveolar proteinosis Pulmonary surfactant p19ARF Deficiency Disrupts Lung and Lipid Homeostasis Resembling the Human Alveolar Proteinosis.