Search

Chronic respiratory inflammation is caused by a sustained influx of macrophages and neutrophils, which leads to tissue remodeling and collagen breakdown. Recently, we have identified collagen-breakdown products that can activate and attract inflammatory cells via the CXC (two cysteines with an inverting amino acid)l and CXC2 receptors (CXCR1 and CXCR2). By using a technique called 'inverted hydropathy', small peptides were synthesized that interact specifically with the responsible collagen-breakdown products and inactivate them. After inactivation, the collagen-breakdown products are no longer able to bind to their receptors. These neutralizing peptides inhibited neutrophil influx, heart hypertrophy and lung emphysema in animal models, and they are likely to be useful in other diseases that are characterized by a chronic inflammation, such as rheumatoid arthritis and inflammatory bowel diseases, where neutrophils are potential target cells. In this opinion article we will present a new hypothesis through which the chronicity and remodeling of tissue of several inflammatory diseases could be explained.

Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastrointestinal tract, and TNF-[alpha] plays a pivotal role in mediating the response. The proinflammatory cytokine TNF-[alpha] is rapidly released by mast cells after degranulation. In the present study, we hypothesized TNF-[alpha] to be an important player in our recently described mast cell-dependent murine model for IBD. The effect of neutralizing anti-TNF-[alpha] MAb was studied on colonic hypersensitivity in mice induced by a skin application of dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dintrobenzene sulfonic acid. Features of the colonic hypersensitivity response included diarrhea, mast cell infiltration and activation, infiltration of inflammatory cells in the colon, colonic patch hypertrophy, and increased mast cell-derived TNF-[alpha] levels in the colon. Anti-TNF-[alpha] MAb could effectively abrogate diarrhea in DNFB-sensitized mice 72 h after the challenge. The numbers of colonic patches and total tissue damage scores were reduced by anti-TNF-[alpha] MAb treatment in DNFB-sensitized mice 72 h after the challenge. Mast cell infiltration and activation remained unaffected by neutralizing anti-TNF-[alpha] MAb. Treatment with the corticosteroid dexamethasone, a frequently used therapeutic treatment in IBD, resuited in a reduction of diarrhea, cellular infiltration, and total tissue damage scores to the same extent as anti-TNF-[alpha] MAb. Additionally, dexamethasone treatment could also reduce total TNF-[alpha] levels in the colon, mast cell numbers, and mast cell activation in both vehicle- and DNFB-sensitized mice 72 h after the challenge. These findings suggest that TNF-[alpha] can play an instrumental role in causing inflammatory responses in the present murine model for IBD downstream from mast cell activation. inflammatory bowel disease; tumor necrosis factor-[alpha]; dexamethasone; dinitrofluorobenzene

We describe the tripeptide neutrophil chemoattractant N-acetyl Pro-Gly-Pro (PGP), derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and in vivo and in vitro blockade of PGP with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic inflammatory diseases., Author(s): Nathaniel M Weathington [1]; Anneke H van Houwelingen [2]; Brett D Noerager [1]; Patricia L Jackson [1]; Aletta D Kraneveld [2]; F Shawn Galin [1]; Gert Folkerts [2]; Frans [...]

The observation that only 50% of patients with adult asthma manifest atopy indicates that other inflammatory mechanisms are likely involved in producing the characteristic features of this disorder; namely reversible airway obstruction, hyperresponsiveness, and pulmonary inflammation. Our recent discovery that antigen-specific lg free light chains (LCs) mediate hypersensitivity-like responses suggests that these molecules may be of import in the pathophysiology of asthma. Using a murine experimental model of nonatopic asthma, we now have shown that an LC antagonist, the 9-mer peptide F991, can abrogate the development of airway obstruction, hyperresponsiveness, and pulmonary inflammation. Further, passive immunization with antigen-specific LCs and subsequent airway challenge can elicit a mast cell-dependent reaction leading to acute bronchoconstriction. These findings, and the demonstration that the concentration of free [kappa] LCs in the sera of patients with adult asthma were significantly increased (as compared with age-matched nonasthmatic individuals), provide previously undescribed insight into the pathogenesis of asthma. In addition, the ability to inhibit pharmacologically LC-induced mast cell activation provides a therapeutic means to prevent or ameliorate the adverse bronchopulmonary manifestations of this incapacitating disorder. mast cells | lung

Byline: Hanneke P. M. van der Kleij (1), Aletta D. Kraneveld (2), Anneke H. van Houwelingen (2), Mirjam Kool (2), Andrys C. D. Weitenberg (2), Frank A. M. Redegeld (2), Frans P. Nijkamp (2) Keywords: mouse; asthma; hyperreactivity; mast cell; neutrophil Abstract: There is increasing evidence that inflammatory mechanisms other than atopy or eosinophilic inflammation may be involved in the pathogenesis of asthma. The mechanisms associated with non-atopic (non-IgE) or neutrophil-mediated asthma are poorly investigated. Non-atopic airway inflammation and hyperresponsiveness was induced in mice by skin sensitization with dinitrofluorobenzene (DNFB) followed by intra-airway challenge with dinitrobenzene sulfonic acid (DNS). Acute bronchoconstriction and mast cell activation were observed shortly after challenge. Increased levels of the major mast cell mediator, TNF-[alpha], were found in the bronchoalveolar lavage fluid of DNFB-sensitized. Mast cells play a key role in the early release of TNF-[alpha] since mast-cell-deficient WBB6F.sub.1-W/W .sup.V mice did not show an increase in TNF-[alpha] release after DNFB-sensitization and DNS challenge compared to their ++ littermates. Features of the late-phase pulmonary reaction included mononuclear and neutrophilic cell infiltration, pulmonary edema, in vitro tracheal hyperreactivity and in vivo airway hyperresponsiveness. These characteristics bear marked similarity with those observed in non-atopic asthmatic patients. Therefore, this model can be used to further study the mechanisms potentially responsible for the development of non-IgE-mediated asthma. Author Affiliation: (1) Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (2) Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands Article History: Registration Date: 08/10/2004

Research was conducted to examine the role of mucosal mast cells in the early component of intestinal delayed-type hypersensitivity (DTH) reaction in the rat. To study the effects of mast cell stabilization on the early events of the DTH reaction, doxantrazole was used in rats. This resulted in a substantial inhibition of the DTH-induced vascular leakage and an increase in serum RMCP II. Results confirm the significant role of mucosal mast cells in early vascular leakage changes of intestinal DTH reactions.

Collection of venous samples and arterial infusion of tracer molecules facilitate the analysis of the permeability of intestinal microvascular permeability in isolated vascularly perfused small intestine of rats. Properties of permeability in the rat are similar to those in the cat. Impairment of endothelium and histamine-incited alterations can be determined in a quantitatively reliable way.

Author(s): Nathaniel M Weathington [1]; Anneke H van Houwelingen [2]; Brett D Noerager [1]; Patricia L Jackson [1]; Aletta D Kraneveld [2]; F Shawn Galin [1]; Gert Folkerts [2]; Frans [...]