The Effect of Tumor Necrosis Factor-?? on Microvascular Permeability in an Isolated, Perfused Lung

Schulman, Carl I.; Wright, Joseph K.; Nwariaku, Fiemu E.; Sarosi, George A.; Turnage, Richard H.

doi:10.1097/00024382-200207000-00014

Cited by 14 publications

(15 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, subcutaneous administration of ONO-1301 significantly attenuated bleomycin-induced increases in total cell counts, neutrophil counts, and total protein level in BAL fluid. Earlier studies have shown that TXA 2 acts as a proinflammatory mediator via enhancement of pulmonary vascular permeability (18,24) and neutrophil adhesion (33). In the present study, TXB 2 , a stable metabolite of TXA 2 , was significantly increased after bleomycin injection, which is consistent with previous studies (2, 8).…”

Section: Discussionsupporting

confidence: 93%

“…Prostacyclin inhibits migration, proliferation, and collagen synthesis in fibroblasts (14, 29). Conversely, thromboxane A 2 (TXA 2 ) promotes fibroblast proliferation, increases pulmonary vascular permeability, and induces lung inflammation (18,21,24). Interestingly, a recent study has demonstrated that the decreased ratio of prostacyclin synthesis to thromboxane synthesis is associated with the development of pulmonary fibrosis (4).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice

Murakami

Nagaya

Itoh

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

. Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 290: L59 -L65, 2006. First published September 9, 2005 doi:10.1152/ajplung.00042.2005The balance between prostacyclin and thromboxane A2 (TXA2) plays an important role in pulmonary homeostasis. However, little information is available regarding the therapeutic potency of these prostanoids for pulmonary fibrosis. We have recently developed ONO-1301, a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. Thus we investigated whether repeated administration of ONO-1301 attenuates bleomycin-induced pulmonary fibrosis in mice. After intratracheal injection of bleomycin or saline, mice were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle. Bronchoalveolar lavage (BAL) and histological analyses were performed at 3, 7, and 14 days after bleomycin injection. In vitro studies using mouse lung fibroblasts were also performed. ONO-1301 significantly attenuated the development of bleomycin-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. ONO-1301 significantly reduced total cell count, neutrophil count, and total protein level in BAL fluid in association with a marked reduction of TXB 2. A single administration of ONO-1301 significantly increased plasma cAMP level for Ͼ2 h. In vitro, ONO-1301 and a cAMP analog dose-dependently reduced cell proliferation in mouse lung fibroblasts. The reduction in cell proliferation by ONO-1301 was attenuated by a protein kinase A (PKA) inhibitor. Furthermore, bleomycin mice treated with ONO-1301 had a significantly higher survival rate than those given vehicle. These results suggest that repeated administration of ONO-1301 attenuates the development of bleomycin-induced pulmonary fibrosis and improves survival in bleomycin mice, at least in part by inhibition of TXA 2 synthesis and activation of the cAMP/PKA pathway. adenosine 3Ј,5Ј-cyclic monophosphate; fibroblast; neutrophil; survival IDIOPATHIC PULMONARY FIBROSIS (IPF) is a life-threatening disease characterized by progressive dyspnea and worsening of pulmonary function (6,22). The pathological features of IPF are fibroblast proliferation with increased amounts of extracellular matrix and varying degrees of persistent inflammation of the alveolar septa (22). Thus a novel therapeutic strategy against these abnormalities may be effective for the treatment of IPF.Prostanoids, which are metabolites of arachidonic acid, are important regulators of pulmonary homeostasis. Prostacyclin inhibits migration, proliferation, and collagen synthesis in fibroblasts (14, 29). Conversely, thromboxane A 2 (TXA 2 ) promotes fibroblast proliferation, increases pulmonary vascular permeability, and induces lung inflammation (18,21,24). Interestingly, a recent study has demonstrated that the decreased ratio of prostacyclin synthesis to thromboxane synthesis is...

show abstract

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice

Murakami

Nagaya

Itoh

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…Besides thrombin, we also evaluated TNF-␣ with respect to lung edema formation in mice. No significant changes were observed up to 120 minutes duration of the experiment (10 ng/mL TNF-␣, data not shown), which is consistent with earlier reports from rats 43 and rabbits. 44 …”

Section: Pde2 Inhibition Reduces Wet-dry Weight Ratio and Lung Permeasupporting

confidence: 92%

Tumor necrosis factor-α–dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability

Seybold

Thomas

Witzenrath

et al. 2005

Blood

122

106

View full text Add to dashboard Cite

The pleiotropic cytokine tumor necrosis factor-␣ (TNF-␣) and thrombin lead to increased endothelial permeability in sepsis. Numerous studies demonstrated the significance of intracellular cyclic nucleotides for the maintenance of endothelial barrier function. Actions of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are terminated by distinct cyclic nucleotide phosphodiesterases (PDEs). We hypothesized that TNF-␣ could regulate PDE activity in endothelial cells, thereby impairing endothelial barrier function. In cultured human umbilical vein endothelial cells (HUVECs), we found a dramatic increase of PDE2 activity following TNF-␣ stimulation, while PDE3 and PDE4 activities remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF-␣ increased PDE2 expression in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Endothelial barrier function was investigated in HUVECs and in isolated mice lungs. Selective PDE2 up-regulation sensitized HUVECs toward the permeability-increasing agent thrombin. In isolated mice lungs, we demonstrated that PDE2 inhibition was effective in preventing thrombin-induced lung edema, as shown with a reduction in both lung wet-to-dry ratio and albumin flux from the vascular to bronchoalveolar compartment. Our findings suggest that TNF-␣-mediated upregulation of PDE2 may destabilize endothelial barrier function in sepsis. Inhibition of PDE2 is therefore of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS). IntroductionSepsis-the systemic inflammatory response to infection-is the most common cause of death among patients in noncoronary intensive care units. 1 Laboratory markers of inflammation include high circulating levels of tumor necrosis factor ␣ (TNF-␣) and other cytokines, as well as activation of the coagulation cascade. 1 Endothelial hyperpermeability is a hallmark of sepsis. TNF-␣ increases endothelial cell permeability 2 with subsequent vascular leakage contributing to severe organ dysfunction such as adult respiratory distress syndrome (ARDS). 3 Half of the sepsis patients develop disseminated intravascular coagulation 2,4 due to a shift toward a procoagulant state with excessive thrombin and fibrin generation. 1 On a cellular level, thrombin changes the shape of endothelial cells and increases endothelial permeability, 5 thereby impairing endothelial barrier function synergistically with TNF-␣. 1,6 Thrombin, the main effector protease of the coagulation cascade, activates endothelial cells directly via protease-activated receptor 1 (PAR1) and PAR4, 7 thereby inducing hyperpermeability and promoting adhesion of platelets and leukocytes, as well as secretion of plateletactivating factor (PAF) and inflammatory cytokines. 8 After binding to one of the various receptors, TNF-␣ mediates activation of diverse signaling pathways, such as the p38 mitogenactivated protein kinase (p38 MAPK), JUN N-terminal kinase (JNK), and nuclear factor kappa B (NF-B). TNF recepto...

show abstract

“…In line with the notion that TNF-α cannot cause edema by itself, TNF-α failed to cause pulmonary edema in isolated perfused lungs within 1 hour [78,79] or 3 hours (own unpublished data). These findings are supported by the observation that in TNF-α perfused lungs antibodies in the perfusate did not reach the alveolar space and vice versa, indicating that the lung vascular barrier was intact [67].…”

Section: Platelet-activating Factor (Paf)supporting

confidence: 71%

Differential Regulation of Lung Endothelial Permeability in Vitro and in Situ

Uhlig

Yang

Waade

et al. 2014

Cell Physiol Biochem

View full text Add to dashboard Cite

In the lungs, increased vascular permeability can lead to acute lung injury. Because vascular permeability is regulated primarily by endothelial cells, many researchers have studied endothelial cell monolayers in culture, in order to understand the pathomechanisms of pulmonary edema. Such studies are based on the assumption that endothelial cells in culture behave like endothelial cells in situ. Here we show that this assumption is largely unfounded. Cultured endothelial cells show profound differences compared to their physiological counterparts, including a dysregulated calcium homeostasis. They fail to reproduce the pulmonary responses to agents such as platelet-activating factor. In contrast, they respond in a Rho-kinase depend fashion to thrombin, LPS or TNF. This is a striking finding for three reasons: (i) in the lungs, none of these agents increases vascular permeability by a direct interaction with endothelial cells; (ii) The endothelial Rho-kinase pathway seems to play little role in the development of pulmonary edema; (iii) This response pattern is similar for many endothelial cells in culture irrespective of their origin, which is in contrast to the stark heterogeneity of endothelial cells in situ. It appears that most endothelial in culture tend to develop a similar phenotyp that is not representative of any of the known endothelial cells of the lungs. We conclude that at present cultured endothelial cells are not useful to study the pathomechanisms of pulmonary edema.

show abstract

The Effect of Tumor Necrosis Factor-?? on Microvascular Permeability in an Isolated, Perfused Lung

Cited by 14 publications

References 35 publications

Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice

Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice

Tumor necrosis factor-α–dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability

Differential Regulation of Lung Endothelial Permeability <b><i>in Vitro</i></b> and <b><i>in Situ</i></b>

Contact Info

Product

Resources

About