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Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model.

ABSTRACT: Background:Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses. Methods:Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs or phosphate-buffered saline was randomly intratracheally administered. Neutrophil count and protein concentration in bronchoalveolar lavage fluid (BALF); lung histology; levels of interleukin (IL)-1?, IL-6, tumor necrosis factor (TNF)-?, and macrophage inflammatory protein-2; and the expression of proliferation cell nuclear antigen (PCNA), caspase-3, and caspase-9 were evaluated at 48 hours after injury. Results:Treatment with MSCs attenuated lung injury in ALI mice by decreasing protein level and neutrophil recruitment into the BALF and improving the histologic change. MSCs also decreased the protein levels of proinflammatory cytokines including IL-1?, IL-6, and TNF-?, but had little effect on the protein expression of PCNA, caspase-3, and caspase-9. Conclusions:Intratracheal injection of bone marrow-derived allogenic MSCs attenuates LPS-induced ALI via immunomodulatory effects.

SUBMITTER: Huh JW

PROVIDER: S-EPMC6786701 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model.

Huh Jin Won JW Kim Won Young WY Park Yun Young YY Lim Chae-Man CM Koh Younsuck Y Kim Mi-Jung MJ Hong Sang-Bum SB

Acute and critical care 20180831 3

<h4>Background</h4>Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses.<h4>Methods</h4>Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs ...[more]

PMID: 31723879

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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition of critically-ill patients, characterized by overwhelming inflammatory responses in the lung. Multiple lines of evidence suggest that the excessive activation of Toll-like receptor 4 (TLR4) plays an important role in this detrimental lung inflammation. Recently, we developed a unique class of peptide-gold nanoparticle (GNP) hybrids that act as potent nano-inhibitors of TLR4 signaling by modulating the process of endosomal acidification. In this study, we aimed to identify the key physiochemical factors that could further strengthen the anti-inflammatory activity of these nano-inhibitors, including the nanoparticle size, the density of peptides coating the nanoparticle surface, as well as the number of the effective amino acid phenylalanine (F) residues in the peptide sequence. Among these factors, we found that the nanoparticle size could significantly affect the TLR4 inhibition. Specifically, the peptide-GNP hybrids with a GNP core of 20 nm (P12(G20)) exhibited the most potent inhibitory activity on TLR4 activation and its downstream cytokine production among those with a GNP core of 13 nm (P12(G13)) and 5 nm (P12(G5)) in THP-1 cell-derived macrophages. This size-dependent anti-inflammatory effect of the hybrid P12 was also observed in a lipopolysaccharide (LPS)-induced mouse model of ALI. It was found that P12(G20) was superior to P12(G13) in prolonging the survival of mice experiencing lethal LPS challenge, decreasing the acute lung inflammation, and alleviating diffuse alveolar damage in the lungs. Interestingly, P12(G20) could also promote long-term tolerance to endotoxin. Detailed mechanistic studies demonstrated that when compared to the smaller P12(G13), the larger P12(G20) had higher cellular uptake and a stronger endosomal pH buffering capacity, contributing to its enhanced therapeutic effects on reducing TLR4 activation in vitro and in vivo. Overall, this study suggests that nanoparticle size is one key factor determining the anti-inflammatory potency of the peptide-GNP hybrids, and the hybrid P12 may serve as a promising, novel class of nanotherapeutics for modulating TLR signaling to treat ALI/ARDS. STATEMENT OF SIGNIFICANCE: We have developed a new class of nanoparticle-based inhibitors (i.e., peptide-GNP hybrids) targeting TLR4 signaling in macrophages. Through evidence-based engineering of the nanoparticle size, surface peptide ligand density and effective amino acid (phenylalanine, F) chain length, we identified a peptide-GNP hybrid, P12(G20), with enhanced anti-inflammatory activity. Specifically, P12(G20) was more potent in reducing inflammation in THP-1 cell-derived macrophages and in a LPS-induced ALI mouse model. More interestingly, P12(G20) facilitated long-term protection against lethal LPS challenge in vivo and induced endotoxin tolerance in vitro. We anticipate that these new hybrids would serve as the next generation anti-inflammatory nano-therapeutics for the treatment of ALI/ARDS or other acute and chronic inflammatory diseases.

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Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model.

Publications

Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model.

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