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Interstitial Lung Disease: Associated with Systemic Sclerosis; New Molecules, New Routes of Administration

Esther F Vicente-Rabaneda1*, Elena González-Sánchez2, Esther San Antonio2, Antonio Muñoz-Callejas2, Ana Urzainqui2*, Santos Castañeda1,2,3

1 Department of Rheumatology, Hospital Universitario de La Princesa, Madrid, Spain

2 Department of Immunology, Hospital Universitario de La Princesa, Madrid, Spain

3 Department of Medicine, Universidad Autónoma de Madrid (UAM), Madrid, Spain

*Corresponding Author:
Esther F Vicente-Rabaneda
Department of Rheumatology, Hospital Universitario de La Princesa, Madrid, Spain E-mail:
Ana Urzainqui
Department of Rheumatology, Hospital Universitario de La Princesa, Madrid, Spain E-mail:

Received: 07-Feb-2023, Manuscript No. JPA-23-88864; Editor assigned: 10- Feb-2023, Pre QC No. JPA-23-88864 (PQ); Reviewed: 24- Feb-2023, QC No. JPA- 23-88864; Revised: 03-Mar-2023, Manuscript No. JPA-23-88864 (R); Published: 10-Mar -2023, DOI: 10.4172/2322-0066.12.1.002

Citation: Vicente-Rabaneda EF, et al. Interstitial Lung Disease: Associated with Systemic Sclerosis; New Molecules, New Routes of Administration. RRJ Pharm Anal. 2023;12:002

Copyright: © 2023 Vicente-Rabaneda EF, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Interstitial Lung Disease (ILD) associated with SSc (SSc-ILD) is one of the most relevant manifestations of the disease, related to loss of quality of life and decreased life expectancy [1,2]. Its pathogenesis is complex and not yet fully elucidated, but microvascular damage inducing activation of endothelial cells, and the activation of B cells, T cells, and monocytes-macrophages leading to release of autoantibodies and proinflammatory cytokines are involved. As a consequence, recruitment of fibroblasts and myofibroblasts, excessive extracellular matrix deposition and development of fibrosis in early stages are increased [3,4]. Current therapeutic strategies for SSc-ILD include immunosuppressive treatments such as mycophenolate mofetil, treatments against inflammatory mechanisms including rituximab or tocilizumab, and anti- fibrotic treatments such as nintedanib or pirfenidone [58]. These systemic therapies are associated with adverse events, which may be enhanced whenever they are used in combination to target both inflammation and fibrosis. In this context, everolimus, an inhibitor of Mammalian Target of Rapamycin (mTOR) kinase activity, whose mechanism of action consists of forming a complex with FK Binding Protein (FKBP)-12, which binds to mTOR, blocking the PI3K/Akt/mTOR pathway appears to be an attractive alternative therapy for SSc-ILD. It has been shown in vitro to present immunoregulatory and anti-proliferative properties on B and T lymphocytes, and fibroblasts, respectively [913].

However, its use is limited by its toxicity, such as dyslipidemia, bone marrow toxicity or pneumonitis. Although the factors associated with everolimus-induced lung toxicity are still poorly understood, recent data suggest an association with STAT3 polymorphisms (rs4796793), the percentage of NKT cells in peripheral blood, and high doses of the drug that have been shown to up-regulate markers of epithelial to mesenchymal transition of bronchial/pulmonary cells both at gene and protein level [1417].

In order to reduce its side effects, everolimus has been encapsulated in PEGylated liposomes decorated with high molecular weight hyaluronic acid (PEG-LipHA+Ev) to vehicle it inside the cells. In vitro studies on cells obtained from Broncho Alveolar Lavage (BAL) and peripheral blood of Connective Tissue Diseases (CTD) patients with ILD have shown that LipHA+EV acts specifically on cells expressing a high rate of CD44 (but not in CD44-negative cells), inhibiting cell proliferation and decreasing phosphorylation level of mTOR, with additional anti-inflammatory effect on alveolar macrophages and lymphocytes [13].

At a preclinical level, we have investigated the efficacy of Lip-HA+Ev in PSGL-1-deficient mice. PSGL-1 is an adhesion molecule expressed on all leukocyte subsets and the main ligand for P-selectin, being PSGL-1/P-selectin interaction relevant not only for acute inflammation, but also for the maintenance of immune homeostasis [1820].

PSGL-1-deficient mice spontaneously develop a SSc-like autoimmune syndrome characterized by fibrosis, vascular damage, autoantibodies, pulmonary arterial hypertension and the spontaneous and progressive development of ILD with aging [21,22]. This animal model resembles human SSc-ILD showing an imbalance in Th1/Treg populations in the lung, with an increase in the percentage of IFN-γ producing B cells and T cells and a reduction of Treg [21].

Interestingly, intratracheal administration of LipHA+Ev directed specifically against lung cells that express CD44 in PSGL-1-deficient mice showed an anti-apoptotic and anti-inflammatory effect, with a decrease in BAL myofibroblasts and the degree of lung inflammation at histological level, as well as a decrease in the severity of peribronchial and interstitial lung fibrosis, from moderate to mild levels[23]. In vitro studies and preclinical evidence of nanotherapy with LipHA+Ev suggest that it is an efficient strategy to treat inflammation and pulmonary fibrosis, opening the possibility of a more specific inhaled route with fewer side effects than the systemic route, for the treatment of inflammatory and fibrosing lung diseases such as SSc-ILD.

Conflict of Interests

The authors have no conflicts of interests related with this manuscript.


We thank the UAM animal facility for animal breeding and care and the Cytometry Unit and Statistical and Methodological Support Unit of the Hospital de La Princesa (Madrid), for technical support.


Our research work targeted nanotherapy with everolimus in PSGL-1 deficient mice was supported by European Innovative Research & Technological Development (ARROW-NANO Project, EURONANOMED AC 2017/00027) and by Spanish Ministry of Health and Instituto de Salud Carlos III (ISCIII) (co-financed by European Regional Development Fund, Fondos FEDER) [grant numbers: AC17-00027, FIS-PI17-01819, and FIS-PI20-01690].