Persistent Generation of Peptido Leukotrienes in Patients with the Adult Respiratory Distress Syndrome

Bernard, Gordon R.; Korley, Victoria; Chee, P.; Swindell, Bridget B.; Ford‐Hutchinson, A. W.; Tagari, Philip

doi:10.1164/ajrccm/144.2.263

Cited by 58 publications

(26 citation statements)

References 7 publications

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“…Furthermore, in nonsurvivors the BAL:plasma ratio for TNF-α, IL-1Β, IL-6 and IL-8 remained unchanged throughout the course of the disease, while it rapidly decreased in survivors [50]. Other groups have also reported nonsurvivors of ARDS or sepsis to have persistent elevation of inflammatory cytokines (table 4) other components of the HDR (i.e., PLA 2 , leukotrines and complement) over time [51,67,[88][89][90]. This finding is important to understanding why treatment modalities of limited duration may be ineffective in ARDS.…”

Section: The Host Defence Response In Ardsmentioning

confidence: 99%

The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment

Gu¹

1996

Eur Respir J

114

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T Th he e r ro ol le e o of f t th he e h ho os st t d de ef fe en nc ce e r re es sp po on ns se e i in n t th he e p pr ro og gr re es ss si io on n a an nd d o ou ut tc co om me e o of f A AR RD DS S: : p pa at th ho op ph hy ys si io ol lo og gi ic ca al l c co or rr re el la at ti io on ns s a an nd d r re es sp po on ns se e t to o g gl lu uc co oc co or rt ti ic co oi id d t tr re ea at tm me en nt t

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Section: The Host Defence Response In Ardsmentioning

confidence: 99%

The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment

Gu¹

1996

Eur Respir J

114

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“…Accordingly, they are thought to play important roles in both normal host defense as well as in a variety of inflammatory disorders (11,12). Pulmonary disorders in which overproduction of LTs is implicated include asthma (13,14) and the adult respiratory distress syndrome (15,16). These lipid mediators are synthesized from arachidonic acid in a multistep pathway initiated by the enzyme 5-LO.…”

Section: Introductionmentioning

confidence: 99%

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Wilborn¹,

Bailie²,

Coffey³

et al. 1996

J. Clin. Invest.

172

140

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Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by inflammation, fibroblast proliferation, and accumulation of extracellular matrix proteins. Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this study, we measured the levels of immunoreactive LTs B 4 and C 4 in homogenates of lung tissue obtained from patients with newly diagnosed, untreated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery for bronchogenic carcinoma. Compared to homogenates of nonfibrotic control lung, homogenates from IPF patients contained 15-fold more LTB 4 and 5-fold more LTC 4 . IPF homogenate levels of LTB 4 were significantly correlated with histologic indices of both inflammation ( r ϭ 0.861) and fibrosis ( r ϭ 0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nuclear membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an "activated" localization pattern was significantly more frequent in IPF lung (19.2 Ϯ 3.3% of cells) than in control lung (9.3 Ϯ 0.9%); this localization pattern was rarely seen (3.2%) in sections from a truly normal transplant donor lung. Consistent with these data, AMs obtained from IPF patients by bronchoalveolar lavage, purified by adherence, and cultured in the absence of a stimulus for 16 h elaborated significantly greater amounts of LTB 4 and LTC 4 than did control AMs obtained from normal volunteers. These data indicate that the 5-LO pathway is constitutively activated in the lungs of patients with IPF, and the AM represents at least one cellular source of LT overproduction in this disorder. We speculate that LTs participate in the pathogenesis of IPF, and their overproduction in this disorder may be amenable to specific pharmacotherapy. (

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“…Alone, a 15-epi-LXA 4 analog does not affect the rate of polyisoprenyl phosphate remodeling in PMN, but coactivation of ALX and LTB 4 receptors prevents LTB 4 -initiated decrements in PSDP (27). These results indicate that LXA 4 and a 15-epi-LXA 4 analog, which inhibit LTB 4 responses (27,29), dramatically switch LTB 4 -initiated polyisoprenyl phosphate signaling via ALX activation ( Figure 2). Together, these findings point to a pivotal diphosphate phosphatase that upon cell activation rapidly converts PSDP to PSMP to unlock proinflammatory signals from counter-regulation by PSDP and serve as a new intracellular target for LXA 4 regulation of LTB 4 signaling.…”

Section: Polyiosprenyl Phosphates As Intracellular Mediators For Recementioning

confidence: 93%

“…LTB 4 and LXA 4 interact with highly specific and distinct G protein-coupled membrane receptors (25,26) to evoke opposing PMN responses, including LXA 4 inhibition of LTB 4 -initiated chemotaxis, adhesion, and transmigration (3). In addition to LXA 4 , 15-epimer-LXs are more potent than LXs, and LXA 4 and 15-epi-LXA 4 interact with the same LXA 4 receptor (ALX) on PMN (25).…”

Section: Polyiosprenyl Phosphates As Intracellular Mediators For Recementioning

confidence: 99%

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Lipid Mediators as Agonists for the Resolution of Acute Lung Inflammation and Injury

Bonnans

Levy

2007

Am J Respir Cell Mol Biol

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Resolution of acute lung inflammation and injury is an active process; it is not merely the absence of proinflammatory signals. Restoration of homeostasis is coordinated by specific mediators and cellular events. In response to injury and inflammatory stimuli, infiltrating leukocytes and tissue-resident cells interact to generate lipoxins (LXs), which are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, LXs display potent antiinflammatory actions. LXA 4 interacts with a G protein-coupled receptor, termed ALX, that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate (PSDP) is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to presqualene monophosphate (PSMP) upon cell activation. PSDP, but not PSMP, directly inhibits phospholipase D, phosphoinositol-3 kinase, and superoxide anion generation. LXs block PSDP turnover in neutrophil membranes to prevent proinflammatory responses. Hence, LX and polyisoprenyl phosphate signaling provide a counter-regulatory circuit to promote resolution of acute lung inflammation. LXA 4 and PSDP mimetics have been prepared with potent protective actions in murine models of asthma and acute lung injury.

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Persistent Generation of Peptido Leukotrienes in Patients with the Adult Respiratory Distress Syndrome

Cited by 58 publications

References 7 publications

The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment

The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Lipid Mediators as Agonists for the Resolution of Acute Lung Inflammation and Injury

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