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RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation.

ABSTRACT: Rosette nanotubes (RNT) are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G?C motif). In this report, the G?C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G?C) and amino acid Lys (K-G?C) which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as K(x)/RGDSK(y)-RNT, where x and y refer to the molar ratios of K-G?C and RGDSK-G?C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous K(x)/RGDSK(y)-RNT on acute lipopolysaccharide (LPS)-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 ?g and/or intravenously with K??/RGDSK¹?-RNT. Here we provide the first evidence that intravenous administration of K??/RGDSK¹?-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K??/RGDSK¹?-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K??/RGDSK¹?-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1?, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K??/RGDSK¹?-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung.

SUBMITTER: Suri SS

PROVIDER: S-EPMC3254261 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation.

Suri Sarabjeet Singh SS Mills Steven S Aulakh Gurpreet Kaur GK Rakotondradany Felaniaina F Fenniri Hicham H Singh Baljit B

International journal of nanomedicine 20111202

Rosette nanotubes (RNT) are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G∧C motif). In this report, the G∧C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G∧C) and amino acid Lys (K-G∧C) which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as K(x)/RGDSK(y)-RNT, ...[more]

PMID: 22238505

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Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation.MethodsWild-type (WT) mice and Spred-2(-/-) mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/-) mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells.ResultsLPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/-) mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-?, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/-) mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells.ConclusionsThe ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.

Dataset Information

RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation.

Publications

RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation.

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