Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB 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.

Hydrogen Sulfide Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite in Sepsis-Evoked Acute Lung Injury via Transient Receptor Potential Vanilloid Type 1 Channel Activation

“…Cross talk between H 2 S and SP raises another possible way that H 2 S may upregulate COX-2 and PGEM in sepsis indirectly through the effects of SP. Indeed, several studies highlighted the significance of SP and COX-2 in various inflammatory states (14)(15)(16)(17). Particularly, SP has been demonstrated to stimulate COX-2 and PGEM upregulation through the ERK-NF-kB pathway in murine burn-induced remote ALI (14).…”

“…Indeed, several studies highlighted the significance of SP and COX-2 in various inflammatory states (14)(15)(16)(17). Particularly, SP has been demonstrated to stimulate COX-2 and PGEM upregulation through the ERK-NF-kB pathway in murine burn-induced remote ALI (14). SP was also demonstrated to augment PGE 2 production in lyme disease-associated inflammatory conditions in murine microglia (46) and to induce COX-2 expression and NF-kB activation in human polymorphonuclear leukocytes (16).…”

“…; Dynastat; Pfizer, New York, NY), a potent and selective COX-2 inhibitor (25-27), or saline was administrated to mice 20 min after CLP. The dosage of capsazepine and parecoxib has been described in the literature and found to be effective in vivo (6,14). DL-propargylglycine (PAG; 50 mg/kg i.p.…”

“…Some studies suggest that COX-2 and PGE 2 might be associated with SP-related inflammatory response (14)(15)(16)(17). Unlike COX-1 that is constitutively expressed, COX-2 is an inducible enzyme stimulated by inflammatory and mitogenic stimuli (8) and has been shown to mediate inflammation by increasing vasodilation, vascular permeability, and edema in numerous respiratory diseases (18)(19)(20).…”

The Burn Wound Microenvironment

“…Application of the COX-2 inhibitor parecoxib in mice attenuates the proinflammatory cytokine response and reduces remote acute lung injury. 71 However, studies of nonsteroidal anti-inflammatory drugs for treatment of burns and similar trauma in humans have typically not focused on the wound healing process itself but on alleviation of pain and fever. 72 The use of corticosteroids has likewise been limited beyond preclinical studies.…”