NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses

Danielle Duma; Daniel Fernandes; Marcelo G. Bonini; Krisztian Stadler; Ronald P. Mason; Jamil Assreuy

doi:10.1016/j.ejphar.2011.05.065

NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses

Danielle Duma, Daniel Fernandes, Marcelo G. Bonini, Krisztian Stadler, Ronald P. Mason, Jamil Assreuy^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7-nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1 ^-/- mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1 ^-/- mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1.

Original language	English (US)
Pages (from-to)	285-292
Number of pages	8
Journal	European Journal of Pharmacology
Volume	668
Issue number	1-2
DOIs	https://doi.org/10.1016/j.ejphar.2011.05.065
State	Published - Oct 1 2011
Externally published	Yes

Funding

We gratefully acknowledge the technical assistance of Adriane S. Madeira. We thank Dr. J. B. Calixto (Universidade Federal de Santa Catarina, Brazil) for the use of some of his equipment. Cristália Pharmaceutical Industries (São Paulo, SP, Brazil) is gratefully acknowledged for the gift of heparin. This work was supported by CNPq , PRONEX , CAPES and FAPESC (Brazil) and the intramural research program of the National Institute of Environmental Health Sciences/NIH (USA) . The authors declare no conflict of interest.

Keywords

NOS-1
Nitric oxide
Sepsis
Skeletal muscle
Vascular hyporesponsiveness

ASJC Scopus subject areas

Pharmacology

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10.1016/j.ejphar.2011.05.065

Cite this

@article{98dbd748f79b43fe8d9c78b0755fd767,

title = "NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses",

abstract = "Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7-nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1 -/- mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1 -/- mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1.",

keywords = "NOS-1, Nitric oxide, Sepsis, Skeletal muscle, Vascular hyporesponsiveness",

author = "Danielle Duma and Daniel Fernandes and Bonini, {Marcelo G.} and Krisztian Stadler and Mason, {Ronald P.} and Jamil Assreuy",

note = "Funding Information: We gratefully acknowledge the technical assistance of Adriane S. Madeira. We thank Dr. J. B. Calixto (Universidade Federal de Santa Catarina, Brazil) for the use of some of his equipment. Crist{\'a}lia Pharmaceutical Industries (S{\~a}o Paulo, SP, Brazil) is gratefully acknowledged for the gift of heparin. This work was supported by CNPq , PRONEX , CAPES and FAPESC (Brazil) and the intramural research program of the National Institute of Environmental Health Sciences/NIH (USA) . The authors declare no conflict of interest.",

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AU - Duma, Danielle

AU - Fernandes, Daniel

AU - Bonini, Marcelo G.

AU - Stadler, Krisztian

AU - Mason, Ronald P.

AU - Assreuy, Jamil

N1 - Funding Information: We gratefully acknowledge the technical assistance of Adriane S. Madeira. We thank Dr. J. B. Calixto (Universidade Federal de Santa Catarina, Brazil) for the use of some of his equipment. Cristália Pharmaceutical Industries (São Paulo, SP, Brazil) is gratefully acknowledged for the gift of heparin. This work was supported by CNPq , PRONEX , CAPES and FAPESC (Brazil) and the intramural research program of the National Institute of Environmental Health Sciences/NIH (USA) . The authors declare no conflict of interest.

PY - 2011/10/1

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N2 - Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7-nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1 -/- mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1 -/- mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1.

AB - Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7-nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1 -/- mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1 -/- mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1.

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NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses

Abstract

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