Ward, R., Krishnan, S.S., Stavrovskaya, I., Sanchez-Gonzalez, D., Agudelo, C.W., Park, S.S., Mai, M., Cai, H., Martinez, J., Cox, K., Rahman, A., Kiang, C., Campos-Azpiroz, M., Geraghty, P., Lopez-Rodriguez, E., Area-Gomez, E., Shmarakov, I., Goldberg, I.J., Foronjy, R.F., and Garcia-Arcos, I.,
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The low-density lipoprotein receptor-related protein 1 (LRP1) performs multiple functions with cell-specific regulation. Genetic variants in LRP1 are associated with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are unknown. Alveolar type 2 cells (T2C) synthesize pulmonary surfactant lipids and are involved in the pathophysiology of COPD. To investigate LRP1 in T2C, we stably transfected a human T2C cell line with LRP1-shRNA (LRP1 knockdown, LRP1 KD) and generated tamoxifen-inducible T2C-specific LRP1 knockout mice (SPC-LRP1−/−). LRP1 KD cells showed decreased surfactant phospholipid secretion and increased neutral lipid accumulation, despite lower expression of lipid metabolic genes. T2C and alveolar surfactant isolated from SPC-LRP1−/− mice showed lower concentrations of phosphatidylcholine than those from Lrp1-floxed controls. At baseline, SPC-LRP1−/− mice had decreased lung compliance and forced vital capacity. After a cigarette smoke exposure challenge, SPC-LRP1−/− mice developed worse fibrotic remodeling than control mice. Both LRP1 KD cells and T2C isolated from SPC-LRP1−/− mice exhibited increased gene expression of detoxification and inflammatory pathways associated with COPD. Finally, the query of public human data showed that T2C from patients with COPD have lower expression of LRP1 and lipid metabolic genes. These data show that LRP1 is needed in T2C for surfactant lipid metabolism and pulmonary function, and suggest that reductions of LRP1 expression promote smoke-associated fibrosis.
