Substance P upregulates cyclooxygenase-2 and prostaglandin E metabolite by activating ERK1/2 and NF-kappaB in a mouse model of burn-induced remote acute lung injury.

Abstract

Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene-deficient mice, which encode for SP, and PPT-A(-/-) mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-κB, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11-7082, which are specific NK1R, MEK-1, and NF-κB antagonists, respectively. Additionally, burn-injured PPT-A(-/-) mice showed suppressed lung COX-2 levels, whereas PPT-A(-/-) mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A(-/-) mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A(-/-) mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-κB, leading to remote ALI after burn.

• Authors: Selena W S Sio, Seah Fang Ang, Jia Lu, Shabbir Moochhala, Madhav Bhatia
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 10 Pg. 6265-76 (Nov 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20926798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Cytokines
• Enzyme Inhibitors
• NF-kappa B
• Prostaglandins E
• Substance P
• Cyclooxygenase 2
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Acute Lung Injury (immunology, metabolism)
• Animals
• Blotting, Western
• Burns (immunology, metabolism)
• Chemokines (biosynthesis, immunology)
• Cyclooxygenase 2 (immunology, metabolism)
• Cytokines (biosynthesis, immunology)
• Disease Models, Animal
• Enzyme Activation (drug effects, immunology)
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (immunology, metabolism)
• Mitogen-Activated Protein Kinase 3 (immunology, metabolism)
• NF-kappa B (immunology, metabolism)
• Prostaglandins E (immunology, metabolism)
• Signal Transduction (immunology)
• Substance P (immunology, metabolism)
• Up-Regulation