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TLR2 activation causes no morbidity or cardiovascular failure, despite excessive systemic nitric oxide production

Anje Cauwels (UGent) , Benjamin Vandendriessche (UGent) , Jennyfer Bultinck (UGent) , Benedicte Descamps (UGent) , Elke Rogge (UGent) , Tom Van Nieuwenhuysen (UGent) , Magdalena Sips (UGent) , Christian Vanhove (UGent) and Peter Brouckaert (UGent)
(2013) CARDIOVASCULAR RESEARCH. 100(1). p.28-35
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
Septic shock is the leading cause of death in intensive care units worldwide, resulting from a progressive systemic inflammatory reaction causing cardiovascular and organ failure. Nitric oxide (NO) is a potent vasodilator and inhibition of NO synthases (NOS) can increase blood pressure in septic shock. However, NOS inhibition does not improve outcome, on the contrary, and certain NO donors may even provide protection. In addition, NOS produce superoxide in case of substrate or cofactor deficiency or oxidation. We hypothesized that excessive systemic iNOS-derived NO production is insufficient to trigger cardiovascular failure and shock. We found that the systemic injection with various synthetic Toll-like receptor-2 (TLR2), TLR3, or TLR9 agonists triggered systemic NO production identical to that of lipopolysaccharide (LPS) or tumour necrosis factor. In contrast to the latter, however, these agonists did not cause hypothermia or any other signs of discomfort or morbidity, and inflammatory cytokine production was low. TLR2 stimulation with the triacylated lipopeptide Pam3CSK4 not only caused identical NO levels in circulation, but also identical iNOS expression patterns as LPS. Nevertheless, Pam3CSK4 did not cause hypotension, bradycardia, reduced blood flow, or inadequate tissue perfusion in the kidney or the liver. We demonstrate that excessive iNOS-derived NO in circulation is not necessarily linked to concomitant cardiovascular collapse, morbidity, or mortality. As such, our data indicate that the central role of iNOS-derived NO in inflammation-associated cardiovascular failure may be overestimated.
Keywords
SEPSIS, IMMUNITY, ENDOTOXIN, LPS, Shock, NOS, TLR2, Hypotension, TOLL-LIKE RECEPTORS, SEPTIC SHOCK, OXIDATIVE STRESS, HEMATOPOIETIC-CELLS, RELAXING FACTOR, SYNTHASE, MICE

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Citation

Please use this url to cite or link to this publication:

Chicago
Cauwels, Anje, Benjamin Vandendriessche, Jennyfer Bultinck, Benedicte Descamps, Elke Rogge, Tom Van Nieuwenhuysen, Magdalena Sips, Christian Vanhove, and Peter Brouckaert. 2013. “TLR2 Activation Causes No Morbidity or Cardiovascular Failure, Despite Excessive Systemic Nitric Oxide Production.” Cardiovascular Research 100 (1): 28–35.
APA
Cauwels, Anje, Vandendriessche, B., Bultinck, J., Descamps, B., Rogge, E., Van Nieuwenhuysen, T., Sips, M., et al. (2013). TLR2 activation causes no morbidity or cardiovascular failure, despite excessive systemic nitric oxide production. CARDIOVASCULAR RESEARCH, 100(1), 28–35.
Vancouver
1.
Cauwels A, Vandendriessche B, Bultinck J, Descamps B, Rogge E, Van Nieuwenhuysen T, et al. TLR2 activation causes no morbidity or cardiovascular failure, despite excessive systemic nitric oxide production. CARDIOVASCULAR RESEARCH. 2013;100(1):28–35.
MLA
Cauwels, Anje, Benjamin Vandendriessche, Jennyfer Bultinck, et al. “TLR2 Activation Causes No Morbidity or Cardiovascular Failure, Despite Excessive Systemic Nitric Oxide Production.” CARDIOVASCULAR RESEARCH 100.1 (2013): 28–35. Print.
@article{4082286,
  abstract     = {Septic shock is the leading cause of death in intensive care units worldwide, resulting from a progressive systemic inflammatory reaction causing cardiovascular and organ failure. Nitric oxide (NO) is a potent vasodilator and inhibition of NO synthases (NOS) can increase blood pressure in septic shock. However, NOS inhibition does not improve outcome, on the contrary, and certain NO donors may even provide protection. In addition, NOS produce superoxide in case of substrate or cofactor deficiency or oxidation. We hypothesized that excessive systemic iNOS-derived NO production is insufficient to trigger cardiovascular failure and shock.
We found that the systemic injection with various synthetic Toll-like receptor-2 (TLR2), TLR3, or TLR9 agonists triggered systemic NO production identical to that of lipopolysaccharide (LPS) or tumour necrosis factor. In contrast to the latter, however, these agonists did not cause hypothermia or any other signs of discomfort or morbidity, and inflammatory cytokine production was low. TLR2 stimulation with the triacylated lipopeptide Pam3CSK4 not only caused identical NO levels in circulation, but also identical iNOS expression patterns as LPS. Nevertheless, Pam3CSK4 did not cause hypotension, bradycardia, reduced blood flow, or inadequate tissue perfusion in the kidney or the liver.
We demonstrate that excessive iNOS-derived NO in circulation is not necessarily linked to concomitant cardiovascular collapse, morbidity, or mortality. As such, our data indicate that the central role of iNOS-derived NO in inflammation-associated cardiovascular failure may be overestimated.},
  author       = {Cauwels, Anje and Vandendriessche, Benjamin and Bultinck, Jennyfer and Descamps, Benedicte and Rogge, Elke and Van Nieuwenhuysen, Tom and Sips, Magdalena and Vanhove, Christian and Brouckaert, Peter},
  issn         = {0008-6363},
  journal      = {CARDIOVASCULAR RESEARCH},
  language     = {eng},
  number       = {1},
  pages        = {28--35},
  title        = {TLR2 activation causes no morbidity or cardiovascular failure, despite excessive systemic nitric oxide production},
  url          = {http://dx.doi.org/10.1093/cvr/cvt168},
  volume       = {100},
  year         = {2013},
}

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