Ct-1501r Selectively Inhibits Induced Inflammatory Monokines in Human Whole Blood Ex Vivo

Rice, Glenn C.; Rosen, Jody; Weeks, Reitha S.; Michnick, John; Bursten, Stuart L.; Bianco, James A.; Singer, Jack W.

doi:10.1097/00024382-199404000-00003

Cited by 45 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rice et al (20) reported that the inhibition of PA generation protects mice from endotoxin lethality, and Abraham et al (39) also reported that the PA generation inhibitor, lisofylline, attenuates lung injury in a mouse hemorrhage model, and the accumulation of neutrophils in lung tissue. Moreover, lisofylline suppresses TNF-␣, IL-1, and IL-6 production elicited by endotoxin, zymosan, and protein A in whole blood ex vivo (40). More recent studies have shown that PA can serve as an inflammatory mediator by inducing IL-8 secretion (41,42).…”

Section: Discussionmentioning

confidence: 97%

Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of Rapamycin-p70 S6 Kinase 1 Pathway

Lim

Choi

Park

et al. 2003

Journal of Biological Chemistry

124

101

View full text Add to dashboard Cite

Macrophages are pivotal effector cells in the innate immune system. When microbial products bind to pathogen recognition receptors, macrophages are activated and release a broad array of mediators, such as cytokines, that orchestrate the inflammatory responses of the host. Phosphatidic acid (PA) has been implicated as an important metabolite of phospholipid biosynthesis and in membrane remodeling and has been further suggested to be a crucial second messenger in various cellular signaling events. Here we show that PA is an essential regulator of inflammatory response. Deleterious effects of PA are associated with the secretion of proinflammatory cytokines, such as tumor necrosis factor-␣, interleukin-1␤, interleukin-6, and the production of nitric oxide, prostaglandin E 2 , which are predominantly released by macrophage Raw264.7 cells. Furthermore, the administration of PA to mice increased the serum cytokine level. Moreover, direct or lipopolysaccharide-induced PA accumulation by macrophages led to the Akt-dependent activation of the mammalian target of rapamycin-p70 S6 kinase 1, a process required for the induction of inflammatory mediators. These findings demonstrate the importance of the role of PA in systemic inflammatory responses, and provide a potential usefulness as specific targets for the development of therapies.

show abstract

Section: Discussionmentioning

confidence: 97%

Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of Rapamycin-p70 S6 Kinase 1 Pathway

Lim

Choi

Park

et al. 2003

Journal of Biological Chemistry

124

101

View full text Add to dashboard Cite

show abstract

“…Lisofylline, like pentoxifylline, has been shown to diminish proinflammatory cytokine expression (TNF-α, IL-1, and IL-6) [129,130] and to inhibit neutrophil accumulation and edema formation [131]. Unlike pentoxifylline, lysofylline partly exerts its anti-inflammatory properties by inhibiting the release of oxidized free fatty acids from cell membranes under oxidative stress.…”

Section: Randomized Controlled Trialsmentioning

confidence: 99%

“…However, there is limited experience in humans to make definite recommendations for clinical use. A small, uncontrolled, phase I pilot study of high-dose pentoxifylline in 6 ARDS patients showed no improvement in either gas exchange or hemodynamic parameters [128].Lisofylline, like pentoxifylline, has been shown to diminish proinflammatory cytokine expression (TNF-α, IL-1, and IL-6) [129,130] and to inhibit neutrophil accumulation and edema formation [131]. Unlike pentoxifylline, lysofylline partly exerts its anti-inflammatory properties by inhibiting the release of oxidized free fatty acids from cell membranes under oxidative stress.…”

mentioning

confidence: 99%

Pharmacotherapy of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Cepkova

Matthay

2006

J Intensive Care Med

170

135

View full text Add to dashboard Cite

Acute lung injury and the acute respiratory distress syndrome are common syndromes with a high mortality rate that affect both medical and surgical patients. Better understanding of the pathophysiology of acute lung injury and the acute respiratory distress syndrome and advances in supportive care and mechanical ventilation have led to improved clinical outcomes since the syndrome was first described in 1967. Although several promising pharmacological therapies, including surfactant, nitric oxide, glucocorticoids and lysofylline, have been studied in patients with acute lung injury and the acute respiratory distress syndrome, none of these pharmacological treatments reduced mortality. This article provides an overview of pharmacological therapies of acute lung injury and the acute respiratory distress syndrome tested in clinical trials and current recommendations for their use as well as a discussion of potential future pharmacological therapies including β 2 -adrenergic agonist therapy, keratinocyte growth factor, and activated protein C. Keywordsacute lung injury; acute respiratory distress syndrome; pulmonary edema; pharmacologic therapiesThe objective of this article is to review pharmacological therapeutic strategies for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Following a brief overview of definitions, epidemiology, pathophysiology, and major nonpharmacological therapies of ALI/ ARDS, we will focus on pharmacological therapies. Given the large number of therapeutic agents tested or implicated for therapy of ALI/ARDS, we attempted to organize this article according to the level of available evidence. The pharmacological therapeutic strategies are divided into 3 sections. The first 2 sections, pulmonary targeted (inhaled) and systemic pharmacological therapy, review all therapeutic agents for which human, phase I, II, or III clinical trials have been conducted. The third section focuses on potential therapies for which there are plausible pathophysiological rationale and preliminary experimental data but no clinical trials. All phase II and III clinical trials are summarized in a table that includes level [1,2] and grade [2,3] of evidence and resulting current recommendations.We searched the MEDLINE database (since 1967), the Cochrane Library, and bibliographies of retrieved articles. The literature search was performed by both authors. In the first 2 sections of this article, we include all therapies for which clinical trials in patients with ALI/ARDS have NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been conducted and all important studies relevant to these therapies. In the third section, potential therapies, we discuss the treatments that are currently the most promising. Definitions and EpidemiologyThe acute respiratory distress syndrome is a clinical syndrome of acute inflammatory lung injury resulting from a variety of etiologies. The syndrome was first described by Ashbaugh and colleagues [4] in 1967 in a series of 12 patients, and...

show abstract

“…Various drugs blocking TNF production by LPS-activated macrophages in vitro have been used to reduce LPS toxicity in vivo, among them are pentoxifylline (PTX) and its derivative lisofylline (12). PTX is a potent phosphodiesterase inhibitor that also affects bacterial translocation (13).…”

Section: Is Oliveira-junior Et Almentioning

confidence: 99%

Effect of pentoxifylline on lung inflammation and gas exchange in a sepsis-induced acute lung injury model

Oliveira-Júnior

Brunialti

Koh

et al. 2006

Braz J Med Biol Res

View full text Add to dashboard Cite

Experimental models of sepsis-induced pulmonary alterations are important for the study of pathogenesis and for potential intervention therapies. The objective of the present study was to characterize lung dysfunction (low PaO 2 and high PaCO 2 , and increased cellular infiltration, protein extravasation, and malondialdehyde (MDA) production assessed in bronchoalveolar lavage) in a sepsis model consisting of intraperitoneal (ip) injection of Escherichia coli and the protective effects of pentoxifylline (PTX). Male Wistar rats (weighing between 270 and 350 g) were injected ip with 10 7 or 10 9 CFU/100 g body weight or saline and samples were collected 2, 6, 12, and 24 h later (N = 5 each group). PaO 2 , PaCO 2 and pH were measured in blood, and cellular influx, protein extravasation and MDA concentration were measured in bronchoalveolar lavage. In a second set of experiments either PTX or saline was administered 1 h prior to E. coli ip injection (N = 5 each group) and the animals were observed for 6 h. Injection of 10 7 or 10 9 CFU/100 g body weight of E. coli induced acidosis, hypoxemia, and hypercapnia. An increased (P < 0.05) cell influx was observed in bronchoalveolar lavage, with a predominance of neutrophils. Total protein and MDA concentrations were also higher (P < 0.05) in the septic groups compared to control. A higher tumor necrosis factor-alpha (P < 0.05) concentration was also found in these animals. Changes in all parameters were more pronounced with the higher bacterial inoculum. PTX administered prior to sepsis reduced (P < 0.05) most functional alterations. These data show that an E. coli ip inoculum is a good model for the induction of lung dysfunction in sepsis, and suitable for studies of therapeutic interventions. Correspondence

show abstract

Ct-1501r Selectively Inhibits Induced Inflammatory Monokines in Human Whole Blood Ex Vivo

Cited by 45 publications

References 0 publications

Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of Rapamycin-p70 S6 Kinase 1 Pathway

Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of Rapamycin-p70 S6 Kinase 1 Pathway

Pharmacotherapy of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Effect of pentoxifylline on lung inflammation and gas exchange in a sepsis-induced acute lung injury model

Contact Info

Product

Resources

About