Thromboxane-induced neutrophil adhesion to pulmonary microvascular and aortic endothelium is regulated by CD18

Wiles, Marc E.; Welbourn, Richard; Goldman, Gideon; Hechtman, Herbert B.; Shepro, David

doi:10.1007/bf00918645

Cited by 43 publications

(19 citation statements)

References 45 publications

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“…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: 83%

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

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. 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...

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Section: Discussionsupporting

confidence: 83%

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

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“…Leukotrienes, potent chemoattractants and coactivators of neutrophils 22 are increased in bronchial fluid and serum of patients with ARDS, but appear to have no predictive value for the development of ARDS. 10 Our study appeared to confirm this finding as no significant changes in serum LTB 4 were found in any patient during the intraoperative and early postoperative course.…”

Section: Discussionmentioning

confidence: 99%

“…Thromboxane is known to stimulate CD18 facilitated adhesion of neutrophils to pulmonary endothelial cells much more than to other endothelial cells. 22 This may lead subsequently to leucocyte margination, sequestration, adhesion, capillary leakage and pulmonary oedema. Furthermore, thromboxane is a potent vasoconstrictor and procoagulant.…”

Section: Discussionmentioning

confidence: 99%

Role of thromboxane and leukotriene B4 in patients with acute respiratory distress syndrome after oesophagectomy

Schilling

Gassmann

Sigurdsson

et al. 1998

British Journal of Anaesthesia

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SummaryWe have studied prospectively the clinical course and serum concentrations of thromboxane B 2 (TxB 2 ) and leukotriene B 4 (LTB 4 ) in patients developing adult respiratory distress syndrome (ARDS) after oesophagectomy. The clinical course was assessed according to a validated ARDS score, and intra-and postoperative measurements of TxB 2 and LTB 4 in pre-and post-pulmonary blood were performed in 18 patients undergoing oesophagectomy for oesophageal carcinoma and 11 control patients undergoing thoracotomy and pulmonary resection. Six of 18 patients undergoing oesophagectomy, but no control patient, developed ARDS. The ARDS score was highest on day 8 after operation. Only patients with ARDS had a significant postoperative increase in postpulmonary, but not pre-pulmonary, TxB 2 concentrations (P : 0.05 vs patients without ARDS).This study provides evidence that TxA 2 , originating from the lungs, was associated with the development of ARDS after oesophageal resection. In view of the high incidence of ARDS after oesophagectomy (10-30%), prophylactic treatment of patients undergoing oesophageal resection with clinically applicable thromboxane synthetase inhibitors may be warranted. (Br. J. Anaesth. 1998; 80: 36-40) Keywords: lung adult respiratory distress syndrome; complications, adult respiratory distress syndrome; surgery, gastrointestinal; hormones, thromboxane; hormones, leukotrienes Adult respiratory distress syndrome (ARDS) is one of the primary contributors to mortality in ICU patients. 1 A wide variety of clinical conditions such as sepsis, burns, trauma 2-4 and major surgery, and oesophageal resections in particular, 5 6 predispose to the development of ARDS. In a meta-analysis of more than 60 000 patients undergoing oesophagectomy, 27% developed ARDS after transthoracic resection and 13% after transhiatal resection. 7 The following factors appear to increase the risk of postoperative ARDS in patients with oesophageal carcinoma: smoking and chronic obstructive pulmonary disease (COPD), transthoracic mobilization of the oesophagus with contusion of the lung during extensive surgery and postoperative (silent) aspiration. 8 Because of the heterogenity of sepsis or trauma patients, it is difficult to acquire comparable study populations for clinical studies of ARDS. In these patients, the triggering insult for ARDS is seldom predictable and it varies greatly in intensity; also, patient conditions such as age, immune and nutritional status and coexisting medical conditions vary widely. Patients undergoing oesophageal resection for oesophageal carcinoma, however, are a homogenous group, with 1-3 of 10 patients developing ARDS. 7 They are usually aged 50-70 yr, the majority have a history of smoking and preoperative weight loss, they are suffering from the same underlying disease, and the duration and magnitude of the insult triggering ARDS (i.e. oesophageal resection) is uniform. In addition, these patients are unique in that they are exposed to a planned triggering factor (i.e. oesophageal resection) ...

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“…TXA 2 , an important lipid mediator of platelets, is involved in platelet-neutrophil interactions (41) and plays a critical role in acid-induced ALI (7,42). TXA 2 induces increased permeability (42) and PMN adhesion to pulmonary endothelial cells (43). TP blocking or thromboxane synthesis inhibition was previously shown to protect from acidinduced PMN sequestration and protein leakage (42,44).…”

Section: Figurementioning

confidence: 99%

Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation

Singbartl²,

2006

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Acute lung injury (ALI) causes high mortality, but its molecular mechanisms are poorly understood. Acid aspiration is a frequent cause of ALI, leading to neutrophil sequestration, increased permeability, and deterioration of gas exchange. We investigated the role of platelet-neutrophil interactions in a murine model of acid-induced ALI. Acid aspiration induced P-selectin-dependent platelet-neutrophil interactions in blood and in lung capillaries. Reducing circulating platelets or blocking P-selectin halted the development of ALI. Bone marrow chimeras showed that platelet, not endothelial, P-selectin was responsible for the injury. The interaction of platelets with neutrophils and endothelia was associated with TXA 2 formation, with detrimental effects on permeability and tissue function. Activated platelets induced endothelial expression of ICAM-1 and increased neutrophil adhesion. Inhibition of platelet-neutrophil aggregation improved gas exchange, reduced neutrophil recruitment and permeability, and prolonged survival. The key findings were confirmed in a sepsis-induced model of ALI. These findings may translate into improved clinical treatments for ALI.

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Thromboxane-induced neutrophil adhesion to pulmonary microvascular and aortic endothelium is regulated by CD18

Cited by 43 publications

References 45 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

Role of thromboxane and leukotriene B4 in patients with acute respiratory distress syndrome after oesophagectomy

Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation

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