Abstract
Collagen Tissue Disease–associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1β, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-β mRNA. However, upon analyzing TGF-β release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients.
Highlights
Collagen Tissue Disease–associated Interstitial Lung Fibrosis (CTD-ILDs) and BronchiolitisObliterans Syndrome (BOS) represent two severe lung fibrogenic disorders involving, respectively, the lung interstitium and small airways, which share several pathogenic mechanisms and a poor long term outcome [1,2]
We have recently demonstrated that primary lung fibroblasts (LFs) isolated from bronchoalveolar lavage (BAL) of CTD-ILD or Bronchiolitis Obliterans Syndrome (BOS) affected patients expressed a high rate of Hyaluronic acid (HA) receptor CD44, and that this receptor represented a relevant and useful molecule with which to develop targeted nanovehicles [7]
We demonstrated that targeted nanovehicles efficiently decreased the viability of LFs in vitro, but in vivo analyses showed a trend of accumulation into alveolar macrophages after long-term inhalatory treatment of rodents [8]
Summary
Collagen Tissue Disease–associated Interstitial Lung Fibrosis (CTD-ILDs) and BronchiolitisObliterans Syndrome (BOS) represent two severe lung fibrogenic disorders involving, respectively, the lung interstitium and small airways, which share several pathogenic mechanisms and a poor long term outcome [1,2]. Collagen Tissue Disease–associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis. Common pathogenic steps include injury of airway epithelium due to immune-inflammatory insults, followed by a trigger of alveolar and bronchiolar epithelial cells transition towards myofibroblasts (epithelial mesenchymal transition, EMT) and a fibro-proliferative phase with uncontrolled extracellular matrix (ECM) deposition. Among ECM components (collagens, elastin, fibronectin, elastic fibers) [3], hyaluronic acid (HA) is the main one that characterizes fibrotic processes [4]. HA is a non-sulfated glycosaminoglycan synthesized by three transmembrane HA synthase (HAS1, HAS2, and HAS3) and binds specific protein partners: CD44 and the receptor for hyaluronan-mediated motility (RHAMM). It has been demonstrated that HA enhances aberrant fibrotic cells motility through the binding with CD44 and RHAMM [5]. Midgley et al showed that EMT TGF-β-dependent of alveolar and bronchiolar epithelial cells was dependent upon HA/CD44/EGFR cascade [6]
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