188宝金博页面版

Lipopolysaccharide-induced lung inflammation is inhibitedby neutralization of GM-CSFRuzica Puljica, Ewald Benediktusa, Christine Plater-Zyberkb, Patrick A. Baeuerleb,Stefan Szelenyia, Kay Brunea,c, Andreas Pahla,?aDepartment of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, GermanybMicromet AG, Staffelseestr. 2, 81477 Munich, GermanycKay Brune is Doerenkamp professor for innovations in animal and consumer protectionReceived 23 July 2006; received in revised form 3 November 2006; accepted 8 November 2006Available online 14 November 2006AbstractGranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)playsanimportantroleinthepathogenesisofacuteandchroniclungdiseaseasamajorregulator governing the functions of granulocyte and macrophage lineage populations. Chronic obstructive pulmonary disease (COPD) is a diseasecharacterized by lung inflammation with accumulation of neutrophils and increased levels of pro-inflammatory cytokines including GM-CSF in thepatient's lungs. We used intranasal administration of lipopolysaccharide (LPS) to mice to induce a disease that resembles COPD with pulmonaryinflammation,neutrophilrecruitmentandreleaseof pro-inflammatory mediatorsin thebronchoalveolar lavage fluidof the diseased mice.2h priorto LPSadministration,miceweresystemicallytreatedwiththemurineGM-CSFneutralizingantibodymAb22E9perintraperitonealinjection.Intranasalchallengewith LPS-induced an increase of total cell number and of neutrophils in the bronchoalveolar lavage fluid. Elevated levels of tumor necrosis factor alpha(TNF-α),keratinocytecytokineandmacrophageinflammatoryprotein-2(MIP-2)werealsoobservedatthistimepoint.GM-CSFwasnolongerdetectablein bronchoalveolar lavage fluid at 24 h due to its early expression with a peak reached 6 h after LPS challenge. Pretreatment of mice with GM-CSFneutralizingantibodydose-dependentlyinhibitedtheaccumulationofneutrophilsandreducedTNF-αandMIP-2proteinlevelsinbronchoalveolarlavagefluid. These data suggest that neutralization of GM-CSF may represent a novel treatment modality for lung inflammation and in particular for COPD.© 2006 Elsevier B.V. All rights reserved.Keywords: Lung; Inflammation; Lipopolysaccharide; GM-CSF; COPD1. IntroductionChronic obstructive pulmonary disease (COPD) is character-ized by reduced lung airflow that is not fully reversible. It is theonly common cause of death that has increased over the last30years(LopezandMurray,1998).Althoughthemajorriskfactoris tobacco smoke, the host factors that are involved in thepathogenesis of COPD have not yet been fully identified. Despiteincreasing insight into the pathophysiological mechanisms ofCOPD, there has been only a limited translation into effectivepharmacotherapy. COPD encompasses emphysema, chronicobstructive bronchitis and a chronic inflammation in the airways(Barnes, 2000; Jeffery, 2000). The local inflammation isdominated by neutrophils, macrophages and T cells, which havebeenfoundinincreasednumbersinlungsofCOPDpatients(Hoggetal.,2004).Ithasbeenproposedthatpro-inflammatorycytokinessuch as interleukin (IL)-8, tumour necrosis factor alpha (TNF-α),macrophage inflammatory protein-2 (MIP-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) play a key rolein the pathophysiology of COPD (Chung, 2001). If so, anta-gonizing these mediators could represent a promising strategy toinhibitlungdestructionwhichinturnwouldhalttheprogressionofairspace enlargement and perhaps airway obstruction in COPD.GM-CSF is a 23-kDa glycoprotein, which appears to be amajor cytokine governing the functions of granulocyte andmacrophage lineage cell populations. Apart from its physio-logical function, there is evidence suggesting a pathological roleof GM-CSF in inflammatory diseases such as COPD. There, thecytokine exerts its pathological effects by priming neutrophilsand monocytes, and inducing secretion of pro-inflammatorycytokines and chemokines (Hartung, 1999).European Journal of Pharmacology 557 (2007) 230–235www.elsevier.com/locate/ejphar?Corresponding author. Tel.: +49 9131 8522002; fax: +49 9131 8522774.E-mail address: pahl@pharmakologie.uni-erlangen.de (A. Pahl).0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.ejphar.2006.11.023