Deregulation of cyclooxygenase and nitric oxide synthase gene expression in the inflammatory cascade triggered by experimental group B streptococcal meningitis in the newborn brain and cerebral microvessels

https://doi.org/10.1016/S0146-0005(99)80070-6Get rights and content

Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of molecular and biological events leading to altered cerebral perfusion, blood-brain barrier disruption, cerebral edema, intracranial hypertension, neurological damage, and even death. Having previously shown that GBS infection impairs cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide (NO), tumor necrosis factor-α) in the brain and cerebral microvessels (MVs) from newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model of renal inflammation. Besides its neurotransmitter role, NO is a potent vasorelaxant whose production is catalyzed by at least three distinct nitric oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20-fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed approximately equal levels of COX-2, lower levels of COX-1 (4-fold) bNOS (5-fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold), and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4-day-old pig brain, but present in great excess in MV. Purified MV showed lower ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in comparison with MV from 6-week-old pigs. Reverse transciption polymerase chain reaction analyses confirmed these results. Treatment with noo-nitro-l-arginine (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and both COX-1 and COX-2 cerebral MV expression. GBS infection (109 colonyforming units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the expression of tumor necrosis factor-α in the cerebrospinal fluid after 2 hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger the expression of iNOS. Our data suggest that there is a net deficiency of NOS isoforms in the immature brain and microvasculature of the 4-day-old piglet and that the differences in expression lead to the immature control of NO and PG production, rendering newborns particularly susceptible to neurological damage because of the undeveloped, nature of their response mechanisms. Moreover, the GBS-induced cascade deregulates the gene expression of interacting inflammatory mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to cerebral hypertension and edema in the early stages of infection. Pharmacological manipulations of the inflammatory cascade could lead to novel thrapeutic approaches for the treatment of GBS meningitis.

References (92)

  • BredtDS et al.

    Nitric oxide synthase regulatory sites: Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites

    J Biol Chem

    (1992)
  • JanssensSP et al.

    Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase

    J Biol Chem

    (1992)
  • MarsdenPA et al.

    Molecular cloning and characterization of human endothelial nitric oxide synthase

    FEBS Lett

    (1992)
  • MageeT et al.

    Cloning of a novel neuronal nitric oxide synthase expressed in penis and lower urinary tract

    Biochem Biophys Res Comm

    (1996)
  • SalterM et al.

    Widespread tissue distribution, species distribution and changes in activity of Ca(2+)-dependent and Ca(2+)-independent, nitric oxide synthases

    FEBS Lett

    (1991)
  • EiglerA et al.

    Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells

    Bioch Bioph Res Commun

    (1993)
  • HoriguchiSR et al.

    Alteration in nciception after intracisternal administration of prostaglandin D2, E2 or F2a to conscious mice

    Eur J Pharmacol

    (1986)
  • KujubuDA et al.

    Expression of the protein product of the prostaglandin synthase-2 gene in mitogen-stimulated Swiss 3T3 cells

    J Biol Chem

    (1993)
  • PeriKG et al.

    Prostaglandin G/H synthase-2 is a major contributor of brain prostaglandins in the newborn

    J Biol Chem

    (1995)
  • BakerCJ et al.

    Group B streptococcal infections

  • TunkelAR et al.

    Bacterial meningitis: recent advances in pathophysiology and treatment

    Ann Int Med

    (1990)
  • PfisterHW et al.

    Mechanisms of brain injury in bacterial meningitis workshop summary

    Clin Infect Dis

    (1994)
  • SandeMA et al.

    Report of a second workshop: Pathophysiology of bacterial meningitis

    Pediatr Infects Dis J

    (1989)
  • OdioCM et al.

    The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis

    N Engl J Med

    (1991)
  • TauberMG

    Brain edema, intracranial pressure and cerebral blood flow in bacterial meningitis

    Pediatr Infect Dis J

    (1989)
  • TauberMG et al.

    Differences of pathophysiology in experimental meningitis caused by three strains of Streptococcus pneumoniae

    J Infect Dis

    (1991)
  • TureenJH et al.

    Loss of cerebrovascular autoregulation in experimental meningitis in rabbits

    J Clin Invest

    (1990)
  • PfisterHW et al.

    Microvascular changes during the early phase of experimental bacterial meningitis

    J Cereb Blood Flow Metab

    (1990)
  • TauberMG et al.

    Toxicity in neuronal cells caused by cerebrospinal fluid from pneumoccocal and gram negative meningitis

    J Infect Dis

    (1992)
  • KimYS et al.

    Brain injury in experimental neonatal meningitis due to group b streptoccoci

    J Neuronpathol Exp Neurol

    (1995)
  • SmithAL et al.

    Cerebral blood flow in experimental haemophilus influenzae b meningitis

    Pediatr Infect Dis J

    (1987)
  • MollerB et al.

    Bioactive and inactive forms of tumor necrosis factor α in spinal cord from patients with meningitis

    J Infect Dis

    (1991)
  • RighiM et al.

    Cytokine production by microglial cel clones

    Eur J Immunol

    (1989)
  • BrederCD et al.

    Regional induction of tumor necrosis factor α expression in the mouse brain after systemic lipopolysaccharide administration

  • JohnsonJ et al.

    Human recombinant tumor necrosis factor alpha infusion mimics endotoxemia in, awake sheep

    J Appl Physiol

    (1989)
  • BeutlerBA

    Orchestration of septic shock by cytokines: The role of cachectin (tumor necrosis factor)

    Prog Clin Biol Res

    (1989)
  • AloisiF et al.

    Production of hemolymphopoietic cytokines (IL-6, IL-8, colony stimulating factors) by normal human astrocytes in response to IL-1 β and tumor necrosis factor

    J Immunol

    (1992)
  • NorrisJG et al.

    Signal transduction pathways mediating IL-6 induction by IL-1 β and tumor necrosis factor α

    J Immunol

    (1994)
  • ChaoCC et al.

    Activated microglia mediate neuronal cell injury via a nitric oxide mechanism

    J Immunol

    (1992)
  • AkassoglouK et al.

    Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice

    J Immunol

    (1997)
  • BazzoniF et al.

    The tumor necrosis factor ligand and receptor families

    New Eng J Med

    (1996)
  • StephensKE et al.

    Tumor necrosis factor causes increased pulmonary permeability and edema: Comparison to septic acute lung injury

    Am Rev Respir Dis

    (1988)
  • GibsonRL et al.

    Group B streptococcus induces tumor necrosis factor in neonatal piglets: Effect of the tumor necrosis factor inhibitor pentoxifylline on hemodynamics and gas exchange

    Am Rev Respir Dis

    (1991)
  • TraceyKJ et al.

    Anticachectin/TNF monoclonal antibodies prevent spetic shock during lethal bacteremia

    Nature

    (1987)
  • HesseDG et al.

    Cytokine appearance in human endotoxemia and primate bacteremia

    Surg Cynecol Obstet

    (1988)
  • MitchieHR et al.

    Detection of circulating tumor necrosis factor alpha after endotoxin administration

    N Engl J Med

    (1988)
  • Cited by (20)

    • Effects of nitric oxide donors on the afferent resting activity in the cephalopod statocyst

      2000, Brain Research
      Citation Excerpt :

      PG receptors were found in the vestibular nucleus [62] and PG is essential for the normal development of the vestibular end organs [70]; PG-E1 therapy may even prevent malfunction of the inner ear caused by microcirculatory disorders [22,65]. The key enzyme in prostaglandin biosynthesis, cyclooxygenase, may be directly activated by NO [21,33], leading to the production of physiologically relevant quantities of PGE2[36]. The biosynthesis of PGE2, which down-regulates LPS-induced iNOS expression [37,50], may be a mechanism by which inflammatory macrophages protect themselves against the cytotoxic effects of NO [73].

    • Group B Streptococcal Neonatal Meningitis

      2022, Clinical Microbiology Reviews
    View all citing articles on Scopus
    View full text