Targeted nanotherapy with everolimus reduces inflammation and fibrosis in scleroderma-related interstitial lung disease developed by PSGL-1 deficient mice.
Background and Purpose: Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc), and current therapies available are of low efficacy or high toxicity. Thus, the identification of innovative less toxic and high efficacy therapeutic approaches to ILD treatment is an...
| Autores: | , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad Alfonso X el Sabio |
| Repositorio: | Repositorio Institucional de la Universidad Alfonso X el Sabio |
| Idioma: | inglés |
| OAI Identifier: | oai:archive.uax.com:20.500.12080/52087 |
| Acceso en línea: | https://hdl.handle.net/20.500.12080/52087 |
| Access Level: | acceso abierto |
| Palabra clave: | everolimus enfermedad pulmonar intersticial nanoterapia PSGL-1 esclerosis sistémica |
| Sumario: | Background and Purpose: Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc), and current therapies available are of low efficacy or high toxicity. Thus, the identification of innovative less toxic and high efficacy therapeutic approaches to ILD treatment is an urgent need. The interaction of P-selectin glyco protein ligand-1 (PSGL-1) with P-selectin initiates leukocyte extravasation and dele tion of the corresponding gene (Selplg) induces a SSc-like syndrome with high incidence of ILD in aged mice. Experimental Approach: Aged PSGL-1 KO (Selplg-/-) mice were used to assess the therapeutic effects of nanotherapy with everolimus, included in liposomes decorated with high MW hyaluronic acid (LipHA+Ev) and administered intratracheally to specifi cally target CD44-expressing lung cells. Key Results: PSGL-1 KO mice had increased numbers of CD45+ and CD45 cells, including alveolar and interstitial macrophages, eosinophils, granulocytes and NK cells, and myofibroblasts in bronchoalveolar lavage (BAL). CD45+ and CD45 cells expressing pro-inflammatory and pro-fibrotic cytokines were also increased. Lungs from PSGL-1 KO mice showed increased immune cell infiltration and apoptosis and exacerbated interstitial and peribronchial fibrosis. Targeted nanotherapy with LipHA+Ev decreased the myofibroblasts in BAL, cells producing proinflammatory and profibrotic cytokines, and the degree of lung inflammation at histology. LipHA+Ev treatment also decreased the severity of peribronchial and interstitial lung fibrosis, from moderate to mild levels. Conclusions and Implications: In PSGL-1 KO mice, targeted nanotherapy with LipHA+Ev was an effective treatment for SSc-ILD, reducing the number of inflamma tory and fibrotic cells in BAL and reducing inflammation and fibrosis in lungs |
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