LPS-Induced Acute Lung Injury is Attenuated by Phosphodiesterase Inhibition: Effects on Proinflammatory Mediators, Metalloproteinases, NF-??B, and ICAM-1 Expression

Coimbra, Raúl; Melbostad, Heidi; Loomis, William; Porcides, Rafael D.; Wolf, Steven E.; Tobar, Maria; Hoyt, David B.

doi:10.1097/01.ta.0000200075.12489.74

Cited by 97 publications

(72 citation statements)

References 66 publications

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“…In accordance, previous animal studies have demonstrated beneficial effects of PDE inhibitors in experimental ARDS by attenuating endotoxin-induced vasomotor dysfunction [17][18][19]. Besides influencing vasoreactivity, PDE inhibitors also have antiinflammatory properties, decreasing pulmonary edema, neutrophil infiltration, reactive oxygen species and levels of proinflammatory mediators in experimental acute lung injury [17][18][19]. These preclinical results suggest that inhibiting PDE may be a potential therapeutic target in ARDS.…”

Section: Introductionsupporting

confidence: 64%

Sildenafil Attenuates Pulmonary Arterial Pressure, but Does Not Improve Oxygenation during ARDS.

Ad¹,

Hofstra²,

Swart³

et al. 2009

A41. Clinical Trials in Icu

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Objective: Pulmonary hypertension is a characteristic feature of acute respiratory distress syndrome (ARDS) and contributes to mortality. Administration of sildenafil in ambulatory patients with pulmonary hypertension improves oxygenation and ameliorates pulmonary hypertension. Our aim was to determine whether sildenafil is beneficial for patients with ARDS. Design: Prospective, open-label, multicenter, interventional cohort study. Setting: Medical-surgical ICU of two university hospitals. Patients: Ten consecutive patients meeting the NAECC criteria for ARDS. Interventions: A single dose of 50 mg sildenafil citrate administered via a nasogastric tube. Main results: Administration of sildenafil in patients with ARDS decreased mean pulmonary arterial pressure from 25 to 22 mmHg (P = 0.022) and pulmonary artery occlusion pressure from 16 to 13 mmHg (P = 0.049). Systemic mean arterial pressures were markedly decreased from 81 to 75 mmHg (P = 0.005). Sildenafil did not improve pulmonary arterial oxygen tension, but resulted in a further increase in the shunt fraction. Conclusion: Although sildenafil reduced pulmonary arterial pressures during ARDS, the increased shunt fraction and decreased arterial oxygenation render it unsuitable for the treatment of patients with ARDS.

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Section: Introductionsupporting

confidence: 64%

Sildenafil Attenuates Pulmonary Arterial Pressure, but Does Not Improve Oxygenation during ARDS.

Ad¹,

Hofstra²,

Swart³

et al. 2009

A41. Clinical Trials in Icu

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show abstract

“…There was no reduction of plasma MMP-9 and the authors did not comment on their reasons for omitting results for plasma MMP-2 levels. The authors analysed nuclear factor (NF)-kB activation using electrophoretic mobility shift assay and found increased activation in the LPS group, suggesting that these effects were mediated via NF-kB-dependent transcription of MMPs [48]. The lack of reduction in MMP-9 in this study may represent the release of stored MMP-9 from neutrophils in the treated group.…”

Section: Other Inhibitorsmentioning

confidence: 79%

“…In a rat model of i.v. LPS-induced lung injury, administration of 5 mg?kg -1 LPS via internal jugular vein caused histologically confirmed lung injury with increased levels of MMP-2 in BAL and MMP-9 in plasma at 4 h [48]. Coadministration of 25 mg?kg -1 PTX, a nonspecific phosphodiesterase inhibitor, reduced severity of lung injury and MMP-2 levels in BAL.…”

Section: Other Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Davey¹,

2011

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) comprise a spectrum of acute inflammatory pulmonary oedema resulting in refractory hypoxaemia in the absence of an underlying cardiogenic cause. There are multiple pulmonary and extrapulmonary causes and ALI/ARDS patients are a clinically heterogeneous group with associated high morbidity and mortality.Inflammatory injury to the alveolar epithelial and endothelial capillary membrane is a central event in the pathogenesis of ALI/ARDS, and involves degradation of the basement membrane. Matrix metalloproteinases (MMPs) have been implicated in a wide variety of pulmonary pathologies and are capable of degrading all components of the extracellular matrix including the basement membrane and key non-matrix mediators of lung injury such as chemokines and cell surface receptors.While many studies implicate MMPs in the injurious process, there are significant gaps in our knowledge of the role of specific proteases at different phases of injury and repair. This article examines the role of MMPs in injury and repair of the alveolar epithelial-endothelial capillary barrier and discusses the potential for MMP modulation in the prevention and treatment of ALI. The need for further mechanistic and in vivo studies to inform appropriate subsequent clinical trials of MMP modulation will be highlighted. KEYWORDS: Acute lung injury, acute respiratory distress syndrome, extracellular matrix, inflammation, matrix metalloproteinases, repair A cute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are part of a disease spectrum associated with high mortality and considerable morbidity. The most recent diagnostic criteria for ALI/ARDS, developed by the 1994 American-European Consensus Conference Committee [1], are based on the gross clinico-radiological findings; acute onset, bilateral infiltrates on chest radiography, absence of left ventricular failure and the ratio of arterial oxygen tension (Pa,O 2 , expressed in mmHg) to inspired oxygen fraction (FI,O 2 ) measuring ,200 (ARDS) or ,300 (ALI) [2][3][4]. However, ALI/ARDS patients are clinically heterogeneous and this definition does not take into account the underlying aetiology or severity of illness reflected by failure of other organ systems [2]. Irrespective of aetiology, the pathogenesis of ALI/ARDS consists of an excessive and inappropriate inflammatory response to a range of pulmonary or extrapulmonary insults, resulting in damage to the alveolar epithelial-endothelial capillary barrier [3,4]. Clinically, this manifests as refractory hypoxaemia and decreased pulmonary compliance. Pathologically, three phases are recognised: an initial acute inflammatory or exudative phase characterised by

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“…However, other unexplored factors might have also accounted for the improved survival of newborn rats treated with PTX, including reduction in activation of nuclear factor-κβ and production of tumor necrosis factor-α, leading to attenuated lung injury (35), and the release of endothelium-derived nitric oxide by PTX in the pulmonary vascular bed, resulting in improved oxygenation (36). There are several potential limitations of this study.…”

Section: Ptx In Neonatal Hyperoxic Lung Injurymentioning

confidence: 88%

Pentoxifylline and prevention of hyperoxia-induced lung injury in neonatal rats

Almario

Peng

et al. 2012

Pediatr Res

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IntroductIon:Oxygen exposure plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD). The phosphodiesterase inhibitor pentoxifylline (PTX) has antiinflammatory and antifibrotic effects in multiple organs. It was hypothesized that PTX would have a protective effect on hyperoxia-induced lung injury (hILI). Methods: Newborn sprague-Dawley rats were exposed to >95% oxygen (O 2 ) and injected subcutaneously with normal saline (Ns) or PTX (75 mg/kg) twice a day for 9 d. Ns-injected, room air-exposed pups were controls. at days 4 and 9, lung tissue was collected to assess edema, antioxidant enzyme (aOe) activities, and vascular endothelial growth factor (VeGF) expression. at day 9, pulmonary macrophage infiltration, vascularization, and alveolarization were also examined. results: at day 9, treatment with PTX significantly increased survival from 54% to 88% during hyperoxia. Treatment with PTX significantly decreased lung edema and macrophage infiltration. PTX treatment increased lung aOe activities including those of superoxide dismutase (sOD), catalase (caT), and glutathione peroxidase (GPX). Furthermore, PTX treatment also increased the gene expression of VeGF189 and VeGF165, increased VeGF protein expression, and improved pulmonary vascularization. dIscussIon: These data indicate that the reduced lung edema and inflammation, increased aOe activities, and improved vascularization may be responsible for the improved survival with PTX during hyperoxia. PTX may be a potential therapy in reducing some of the features of BPD in preterm newborns.

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LPS-Induced Acute Lung Injury is Attenuated by Phosphodiesterase Inhibition: Effects on Proinflammatory Mediators, Metalloproteinases, NF-??B, and ICAM-1 Expression

Abstract: Phosphodiesterase inhibition by PTX attenuates LPS-induced end-organ injury. In addition, proinflammatory cytokine production is also downregulated, likely because of the marked attenuation of NF-kappaB DNA binding and activation.

Cited by 97 publications

References 66 publications

Sildenafil Attenuates Pulmonary Arterial Pressure, but Does Not Improve Oxygenation during ARDS.

Sildenafil Attenuates Pulmonary Arterial Pressure, but Does Not Improve Oxygenation during ARDS.

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Pentoxifylline and prevention of hyperoxia-induced lung injury in neonatal rats

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LPS-Induced Acute Lung Injury is Attenuated by Phosphodiesterase Inhibition: Effects on Proinflammatory Mediators, Metalloproteinases, NF-??B, and ICAM-1 Expression

Abstract: Phosphodiesterase inhibition by PTX attenuates LPS-induced end-organ injury. In addition, proinflammatory cytokine production is also downregulated, likely because of the marked attenuation of NF-kappaB DNA binding and activation.

Cited by 97 publications

References 66 publications

Sildenafil Attenuates Pulmonary Arterial Pressure, but Does Not Improve Oxygenation during ARDS.

Sildenafil Attenuates Pulmonary Arterial Pressure, but Does Not Improve Oxygenation during ARDS.

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Pentoxifylline and prevention of hyperoxia-induced lung ­injury in neonatal rats

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Product

Resources

About

Pentoxifylline and prevention of hyperoxia-induced lung injury in neonatal rats