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Methods for attenuating release of inflammatory mediators and peptides useful therein

A technology of mediators and inflammation, applied in the field of modulation and regulation of intracellular signaling mechanisms that regulate the secretion of inflammatory mediators from inflammatory cells, can solve the problems of insufficiently revealing regulatory molecules and specific pathways, etc.

Active Publication Date: 2009-08-26
BIOMARK PHARMACEUTICALS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Leukocytes are known to release these granules via the exocytosis mechanism (see for example Burgoyne RD, Morgan A. Secretory granule exocytosis. Physiol Rev 2003; 83:581-632; and Logan MR, Odemuyiwa SO, Moqbel R. Understanding exocytosis in immune and inflammatory cells: the molecular basis of mediatorsecretion.J Allergy Clin Immunol 2003;111:923-932), but the regulatory molecules and specific pathways involved in this exocytosis process have not been fully revealed

Method used

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  • Methods for attenuating release of inflammatory mediators and peptides useful therein
  • Methods for attenuating release of inflammatory mediators and peptides useful therein
  • Methods for attenuating release of inflammatory mediators and peptides useful therein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0452] Example 1: Study on the secretion of inflammatory mediators

[0453] Four different white blood cell types or models that secrete specific granular components in response to phorbol ester-induced PKC activation were used. Neutrophils were isolated from human blood and tested for the release of MPO from these cells in vitro. The release of membrane-bound inflammatory mediators from a commercial human leukocyte cell line was also evaluated. The human promyelocytic cell line HL-60 clone 15 was used to analyze the release of EPO (Fischkoff SA. Graded increase in probability of eosinophilic differentiation of HL-60 promyelocyticleukemia cells induced by culture under alkaline conditions. Leuk Res 1988; 12: 679-686; Rosenberg HF , Ackerman SJ, Tenen DG. Human eosinophilcationic protein: molecular cloning of a cytotoxin and helminthotoxin withribonuclease activity. J Exp Med 1989; 170: 163-176; Tiffany HL, Li F, Rosenberg HF. Hyperglycosylation of eosinophil ribonucleases in a cel...

Embodiment 2

[0490] Example 2: MANS and related peptides inhibit lipopolysaccharide (LPS)-induced lung inflammation in vivo

[0491] This example is basically carried out according to the method described in the following documents: Cox, G, Crossley, J., and Xing, Z.; Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in ViVo; Am.J.Respir.Cell Mol. Biol. 12: 232-237, 1995; Hirano S., Quantitative time-course profiles of bronchoalveolar laVage cells following intratracheal instillation of lipopolysaccharide in mice, Ind. Health 35: 353-358, 1997; and Ulich TR, WatsonLR, Yin SM , Guo KZ, Wang P, Thang H, and del Castillo, J. Am. J. Pathol. 138: 1485-1496, 1991.

[0492] Therefore, 6 to 7-week-old CD1 female mice weighing 15-20 g were obtained from Charles River Laboratories, and 5 mice per cage were raised in groups. The animals received ad libitum standard rodent diet and filtered water. Follow NIH guidelines to keep animals at standard ...

Embodiment 3

[0507] Example 3: Ozone-induced COPD mouse model

[0508] Oxidative stress caused by chemical irritants such as ozone is a widely recognized feature of chronic obstructive respiratory disease (COPD). See: Repine JE, Bast A, Lankhorst I, and the Oxidative Stress Study Group, Am.J.Respir.Crit.Care Med.156:341-357, 1997; and also Harkema JR and Hotchkiss JA, Toxicology Letters, 68:251- 263, 1993.

[0509] 10-week-old Balb / C female mice were obtained from Charles River Laboratories, and 5 mice per cage were raised in groups according to NIH guidelines. The animals received ad libitum standard rodent diet and filtered water. Mice in 3 treatment groups, 5 in each group, were anesthetized by intraperitoneal injection of ketamine (100mg / kg) and xylazine (20mg / kg), and then pretreated by intratracheal administration of 25 μL of the following treatment: PBS only; Or 1.0 mM MANS peptide solution dissolved in PBS; or 1.0 mM acetylated MANS fragment peptide Ac-GAQFSKTAAK (named acetylated SEQ ...

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Abstract

The present invention includes methods of inhibiting or suppressing cellular secretory processes. More specifically the present invention relates to inhibiting or reducing the release of inflammatory mediators from inflammatory cells by inhibiting the mechanism associated with the release of inflammatory mediators from granules in inflammatory cells. In this regard, the present invention discloses an intracellular signaling mechanism that illustrates several novel intracellular targets for pharmacological intervention in disorders involving secretion of inflammatory mediators from vesicles in inflammatory cells. Peptide fragments and variants thereof of MANS peptide as disclosed in the present invention are useful in such methods.

Description

[0001] Cross-references to related applications [0002] This application claims the priority of U.S. Patent Application No.: 60 / 833,239 filed on July 26, 2006, the entire content of which is hereby incorporated into this application by reference. Technical field [0003] The present invention relates to peptides or peptide compositions and methods of using them to reduce (or inhibit or reduce) the stimulated release of inflammatory mediators from inflammatory cells during inflammation. The present invention also relates to the use of these peptides or peptide compositions for modulating the intracellular signal mechanism that regulates the secretion of inflammatory mediators from inflammatory cells. Background technique [0004] Inflammatory leukocytes synthesize a variety of inflammatory mediators. These inflammatory mediators are separated in the cell and stored in cytoplasmic membrane-bound particles. Examples of such mediators include, but are not limited to, myeloperoxidase ...

Claims

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Application Information

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IPC IPC(8): A01N37/18A61K38/08
CPCA61K38/17A61K38/08A61K38/10A61K38/16A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P11/08A61P17/00A61P17/06A61P17/10A61P19/02A61P25/04A61P29/00A61P37/02A61P37/06A61P37/08A61P43/00A61K45/06
Inventor I·帕里克
Owner BIOMARK PHARMACEUTICALS LTD
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