Proinflammatory events in right ventricular damage during pulmonary embolism: effects of treatment with ketorolac in rats.

Abstract

Right ventricular (RV) damage contributes to poor clinical outcome after pulmonary embolism (PE). Our studies show that neutrophils contribute to RV dysfunction in rat PE. Present studies examine effects of the nonsteroidal anti-inflammatory drug, ketorolac, upon RV inflammation and dysfunction. RV inflammatory gene expression significantly increased 6 and 18 hours after PE [cytokine-induced neutrophil chemoattractant-1 (CINC-1) 18-fold and 24-fold; cyclooxygenase-2 21-fold and 32-fold]. Eighteen hours after PE, there was significant upregulation of adhesion molecules (selectin E 18-fold; intercellular adhesion molecule 1 14-fold), influx of neutrophils (myeloperoxidase activity 21-fold), depressed RV function (RV peak systolic pressure = 24 +/- 3 vs. 40 +/- 1 mm Hg; maximum rate of pressure development = 444 +/- 79 vs. 1533 +/- 146; maximum rate of pressure decrease = -357 +/- 50 vs. -651 +/- 44), and release of cardiac troponin I (7.8 +/- 1.9 ng/mL) compared with vehicle. Ketorolac (10 mg/kg, intraperitoneally) significantly reduced expression of CINC-1, cyclooxygenase-2, selectin E, and intercellular adhesion molecule 1, lowered neutrophil influx, improved RV function (RV peak systolic pressure was 34 +/- 3 mm Hg; maximum rate of pressure development = 1288 +/- 146; maximum rate of pressure decrease = -611 +/- 92), and marginally reduced cardiac troponin I release (P < 0.07) compared with PE alone. Ketorolac reduced CINC-1 stimulated chemotaxis of isolated neutrophils. PE converted cardiac tissue into a proinflammatory phenotype. Ketorolac reduced RV inflammatory genes, reduced neutrophil influx, and improved RV function in rat PE.

• Authors: John A Watts, Michael A Gellar, Lori K Stuart, Maria Obraztsova, Jeffrey A Kline
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 54 Issue 3 Pg. 246-52 (Sep 2009) ISSN: 1533-4023 [Electronic] United States
• PMID: 19620882 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Chemokine CXCL1
• Cxcl1 protein, rat
• Cyclooxygenase Inhibitors
• E-Selectin
• RNA, Messenger
• Troponin I
• Intercellular Adhesion Molecule-1
• Peroxidase
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Ketorolac

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Chemokine CXCL1 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase Inhibitors (therapeutic use)
• E-Selectin (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Inflammation (drug therapy, physiopathology)
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Ketorolac (therapeutic use)
• Male
• Myocardial Contraction (drug effects)
• Neutrophil Infiltration (drug effects)
• Peroxidase (metabolism)
• Pulmonary Embolism (physiopathology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Time Factors
• Troponin I (metabolism)
• Ventricular Dysfunction, Right (metabolism, physiopathology)
• Ventricular Pressure (drug effects)