Cyclooxygenase-2–Dependent and Thromboxane-Dependent Vascular and Bronchial Responses are Regulated via p38 Mitogen-Activated Protein Kinase in Control and Endotoxin-Primed Rat Lungs

  title={Cyclooxygenase-2–Dependent and Thromboxane-Dependent Vascular and Bronchial Responses are Regulated via p38 Mitogen-Activated Protein Kinase in Control and Endotoxin-Primed Rat Lungs},
  author={Monika Ermert and Daniel Kuttner and Nils Eisenhardt and Christian Dierkes and Werner Seeger and Leander Ermert},
  journal={Laboratory Investigation},
Mitogen-activated protein kinases (MAPKs) are part of an intracellular signaling machinery consisting of three known distinct pathways, each leading to activation of a different protein kinase: p38, ERK (extracellular signal-regulated kinase), or JNK (c-Jun N-terminal kinase). We investigated the role of the p38 MAPK pathway in the phenomenon of lung endotoxin “priming”: incubation of perfused rat lungs with lipopolysaccharide (LPS) for 2 hours results in drastically enhanced cyclooxygenase-2… Expand
Prostaglandin E₂ protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction.
PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered after bleomyin challenge. Expand
Endotoxin-induced activation of equine platelets: evidence for direct activation of p38 MAPK pathways and vasoactive mediator production
In vivo, LPS stimulates TxA2 production and p38 MAPK phosphorylation in equine platelets and leukocytes at a concentration within a similar range to those reported in clinical endotoxaemia, suggesting that LPS-induced eicosanoid production in the early phase of clinical endotoxicemia may involve direct effects of LPS upon platelets, mediated via activation of p38MAPK. Expand
Thromboxane promotes smooth muscle phenotype commitment but not remodeling of hypoxic neonatal pulmonary artery
It is concluded that thromboxane does not initiate phenotypic dedifferentiation and proliferative activation in PPHN PA and neonatal pulmonary artery (PA) myocytes in tissue culture. Expand
Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes.
Hypoxia has a priming effect on neonatal pulmonary arterial myocytes, resulting in increased resting Ca2+, thromboxane hypersensitivity, and hyperreactivity, and it is concluded that hypoxia increases agonist-induced TP-R-linked IP3 pathway activation. Expand
Thromboxane hypersensitivity in hypoxic pulmonary artery myocytes: altered TP receptor localization and kinetics.
It is concluded that the TP-R is normally desensitized in the neonatal pulmonary circuit by PKA-mediated regulatory phosphorylation, decreasing ligand affinity and coupling to Galphaq; this protection is lost following hypoxic exposure. Expand
Milrinone attenuates thromboxane receptor‐mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes
This work has hypothesized that prostacyclin receptor activity induces TP receptor phosphorylation and decreases ligand affinity, and that TP receptor sensitization in hypoxic myocytes is due to IP receptor inactivation; and that this would be reversible by the cAMP‐specific phosphodiesterase inhibitor milrinone. Expand
Inhaled carbon monoxide confers antiinflammatory effects against ventilator-induced lung injury.
It is demonstrated that inhaled CO exerts antiinflammatory effects in VILI via the p38 mitogen-activated protein kinase pathway but independent of activator protein-1 and nuclear factor-kappaB pathways. Expand
Effects of budesonide and N-acetylcysteine on acute lung hyperinflation, inflammation and injury in rats.
It is demonstrated that LPS in a concentration-dependent pattern induces acute lung hyperinflation measured by excised lung gas volume, lung injury indicated by increased lung weight and lung inflammation characterized by the infiltration of leukocytes and neutrophils and the production of cytokines and chemokines in bronchoalveolar lavage fluid (BALF). Expand
N-acetylcysteine advancement of surfactant therapy in experimental meconium aspiration syndrome: possible mechanisms.
NAC suppressed IL-8 and IL-beta formation and thus seems to be favorable agent for improving surfactant therapy in MAS, and was the only treatment which prevented neutrophil migration into the lungs, oxidative damage and lung edema. Expand


p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes*
p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown thatExpand
Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide: mediation through both mitogen-activated protein kinase and NF-kappaB signaling pathways in macrophages.
Results indicate that the activation of NF-kappaB is required to induce the expression of COX-2 in LPS-stimulated RAW 264.7 cells. Expand
Mitogen-activated Protein Kinases Mediate Activator Protein-1-dependent Human Inducible Nitric-oxide Synthase Promoter Activation*
P38- and ERK-dependent pathways, through effects on the AP-1 complex, activate the hiNOS promoter in cells stimulated with CM or LPS/IFN-γ-stimulated cells. Expand
Endotoxin priming of the cyclooxygenase-2-thromboxane axis in isolated rat lungs.
The propensity of LPS-primed lungs to respond with enhanced vasoconstriction, edema formation, and bronchoconstrictor responses to a secondarily applied stimulus proceeds nearly exclusively via COX-2 and increased Tx formation, with TNF-alpha generation being involved in the change in bronchomotor reactivity in the presence of plasma constituents. Expand
Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide.
It is reported that exposure of neutrophils to LPS results in the phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase, occurring in a concentration-dependent manner, with maximum response at 20 to 25 min. Expand
Induction of Cyclooxygenase-2 by the Activated MEKK1 → SEK1/MKK4 → p38 Mitogen-activated Protein Kinase Pathway*
It is found that overexpression of ΔMEKK1 (a constitutively active truncation mutant of MEKK1 containing the C-terminal 324 amino acids) increases Cox-2 expression and PGE2 production which is completely blocked by SC68376, a pharmacologic inhibitor of p38 MAPK. Expand
Both Erk and p38 kinases are necessary for cytokine gene transcription.
It is suggested that activation of both the Erk and p38 kinase pathways is necessary for optimal cytokine gene expression in LPS-stimulated human AM, and that the MAPK pathways play a critical role in the inflammatory response that occurs in sepsis-induced acute lung injury. Expand
Involvement of p38 mitogen‐activated protein kinase in lipopolysaccharide‐induced iNOS and COX‐2 expression in J774 macrophages
A crucial role of p38 MAPK is suggested in regulation of the transcriptional level of endotoxin LPS‐induced iNOS and COX‐2 protein expression in J774 macrophages. Expand
Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*)
It is demonstrated that p38, like JNK, is activated by treatment of cells with pro-inflammatory cytokines and environmental stress and the mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182. Expand
Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury.
The main isoform present in these cells and thought to be responsible for the observed phenomenon, is the alpha isoform, and it is shown that p38beta does not contribute to the total p38 signal in extracts, and there is no detectable beta isoform. Expand