Deletion of microsomal prostaglandin E synthase-1 does not alter ozone-induced airway hyper-responsiveness.

Abstract

Nonsteroidal anti-inflammatory drugs ameliorate pain and fever by inhibiting cyclooxygenase (COX) and suppressing prostanoid formation. Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes formation of PGE(2) from the COX product PGH(2) and has emerged as a therapeutic target. Inhibition of mPGES-1, however, renders the PGH(2) substrate available for diversion to other PG synthases. To address the possibility that substrate diversion augments formation of PGs that might modulate bronchial tone, we assessed the impact of mPGES-1 deletion in a mouse model of ozone-induced airway hyper-responsiveness. Ozone exposure increased total lung resistance to inhaled methacholine in wild-type mice. Deletion of mPGES-1 had little effect on total lung resistance in either naive or ozone-exposed animals. The carbachol-induced narrowing of luminal diameter in intrapulmonary airways of lung slices from acute ozone-exposed mice was also unaltered by mPGES-1 deletion. Likewise, although concentrations of PGE(2) were reduced in bronchoalveolar lavage fluid, whereas 6-keto-PGF(1alpha), PGD(2), and PGF(2alpha), all were increased, deletion of mPGES-1 failed to influence cell trafficking into the airways of either naive or ozone-exposed animals. Despite biochemical evidence of PGH(2) substrate diversion to potential bronchomodulator PGs, deletion of mPGES-1 had little effect on ozone-induced airway inflammation or airway hyper-responsiveness. Pharmacologically targeting mPGES-1 may not predispose patients at risk to airway dysfunction.

• Authors: Miao Wang, Philip R Cooper, Meiqi Jiang, Hengjiang Zhao, Yiqun Hui, Yubing Yao, Joshua C Tate, Gautam Damera, John A Lawson, William F Jester Jr, Angela Haczku, Reynold A Panettieri Jr, Garret A FitzGerald
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 334 Issue 1 Pg. 63-8 (Jul 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20371706 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Prostaglandins
• Methacholine Chloride
• Ozone
• Carbachol
• Intramolecular Oxidoreductases
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Dinoprostone

Topics

• Airway Resistance (drug effects)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects)
• Carbachol (pharmacology)
• Cell Differentiation (drug effects)
• Dinoprostone (biosynthesis)
• Female
• Gene Deletion
• Intramolecular Oxidoreductases (deficiency, physiology)
• Methacholine Chloride (pharmacology)
• Mice
• Mice, Knockout
• Microsomes (enzymology)
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects)
• Ozone (pharmacology)
• Prostaglandin-E Synthases
• Prostaglandins (biosynthesis)
• Respiratory System (drug effects, enzymology, immunology, metabolism)