Inhibition of CINC-1 decreases right ventricular damage caused by experimental pulmonary embolism in rats.
Right ventricular (RV) dysfunction is a strong risk factor for poor clinical outcome following pulmonary embolism (PE), the third most prevalent cardiovascular disease. Previous studies in our laboratory demonstrated that RV failure during PE is mediated, in part, by neutrophil-dependant cardiac inflammation. In this study we use DNA microarray analysis of gene expression to demonstrate that PE results in increased expression of the CXC chemokines CINC-1 and CINC-2 between 6 and 18 h after the start of PE in a rat model of PE. Neutrophils accumulate in RV tissue by 18 h, and this inflammation is associated with decreased right heart function. Treatment of rats with Abs to CINC-1 significantly suppressed neutrophil accumulation in RVs during PE (52% reduction in tissue myeloperoxidase) and ameliorated RV failure. In addition, plasma concentration of cardiac troponin I, an established diagnostic marker for cardiac damage, was reduced by 90%. These results suggest that selective anti-inflammatory therapies targeted at neutrophil chemoattractants will reduce cardiac inflammation and reduce RV damage in the setting of PE.
Zagorski
John
J
Department of Emergency Medicine, James G Cannon Research Center, Carolinas Medical Center, Charlotte, NC 28203, USA.
Gellar
Michael A
MA
Obraztsova
Maria
M
Kline
Jeffrey A
JA
Watts
John A
JA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000937:Antigen-Antibody Reactions; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007249:Inflammation; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011655:Pulmonary Embolism / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D019210:Troponin I / Q000097:blood; D018497:Ventricular Dysfunction, Right / Q000276:immunology* / Q000473:pathology
D000906:Antibodies; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; C513294:Cxcl3 protein, rat; D019210:Troponin I; D020780:Matrix Metalloproteinase 9