Pharmacotherapy of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Cardiovascular Research Institute, University of California San Francisco, CA 94143-0130, USA.
Journal of Intensive Care Medicine (Impact Factor: 7.21). 05/2006; 21(3):119-43. DOI: 10.1177/0885066606287045
Source: PubMed


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 beta(2)-adrenergic agonist therapy, keratinocyte growth factor, and activated protein C.

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    • "ALI and ARDS are associated with increased pulmonary morbidity and mortality and increased burdens of medical care. Treatments for ALI/ARDS patients are primarily supportive and include lung protection strategies, antibiotics targeting the cause of infection, and restrictive fluid management [3] [4] [5]. No effective treatment exists for ARDS. "
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    ABSTRACT: Acute lung injury (ALI) is associated with an inflammation-mediated process, and the transcription factor, Krüppel-like factor 5 (KLF5), might play a crucial role in inflammatory lung disease. In this study, we evaluated KLF5, reactive oxygen species (ROS), and inflammatory responses in a lipopolysaccharide- (LPS-) induced ALI model to elucidate the role of KLF5 in ALI. Our data indicated that LPS upregulates proinflammatory cytokine expression in human bronchial epithelial cells in a dose-dependent manner. We observed upregulated KLF5 protein expression in human bronchial epithelial cells exposed to LPS, with peak expression 1 h after LPS treatment, and subsequent upregulation of p65 protein expression and p65 phosphorylation at Ser276. These results indicate that KLF5 mediates proinflammatory cytokine expression by upregulating nuclear factor-kappaB (NF-κB) phosphorylation at p65 in response to LPS. LPS treatment also increased ROS production and simultaneously upregulated KLF5 expression and NF-κB translocation. N-acetylcysteine significantly reduced ROS levels and KLF5 and NF-κB translocation in nuclear extracts. Therefore, N-acetylcysteine pretreatment before LPS exposure reduces ROS, downregulates KLF5 expression, and subsequently reduces inflammatory responses by scavenging ROS. Overall, our study results indicate that KLF5 mediates proinflammatory cytokine expression through upregulation of NF-κB phosphorylation at p65 in LPS-induced ALI.
    Full-text · Article · Aug 2014 · Mediators of Inflammation
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    • "There is an extensive crosstalk between inflammation, activated coagulation and depressed fibrinolysis, so that alveolar fibrin depositions and small vessel thrombi are thought to contribute and perpetuate alveolocapillary inflammation, pulmonary vascular injury and barrier dysfunction [3], [8]–[11]. The alveolar and systemic levels of naturally occurring anticoagulants, such as activated protein C (APC), may be depressed because of consumption, impaired synthesis and degradation, and inhibitors of fibrinolysis may be increased, and both phenomena may be associated with pulmonary and remote organ dysfunction and mortality [8], [9]. "
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    ABSTRACT: Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome. A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria. A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38). The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others. Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or non-invasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market. There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering. Nederlands Trial Register ISRCTN 52566874.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "The inflammatory process of ALI can be classified into three stages: exudative, proliferative, and fibrotic stages [4, The considerable progress made through the use of molecular and cellular assays together with knockout and transgenic animals has contributed significantly to the understanding of the genetic, tissue-specific, and immunological factors that contribute to the development of ALI [45] [46] [47] [48] [49] [50] [51] [52]. Nevertheless, no therapeutic agents have demonstrated a clear benefit in ALI treatment [41], and corticosteroids have been used for treatment of ALI for many years [18] [53]. Besides, the disappointing results of a series of clinical trials treatment of ALI or patients at risk for ARDS using corticosteroids as well as the increase of the risk of infection and other adverse effects, the administration of corticosteroids might improve the injured tissue due to their anti-inflammatory effect [54]. "
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    ABSTRACT: Acute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. ALI is characterized by increased permeability of the alveolar-capillary membrane, edema, uncontrolled neutrophils migration to the lung, and diffuse alveolar damage, leading to acute hypoxemic respiratory failure. Although corticosteroids remain the mainstay of ALI treatment, they cause significant side effects. Agents of natural origin, such as medicinal plants and their secondary metabolites, mainly those with very few side effects, could be excellent alternatives for ALI treatment. Several studies, including our own, have demonstrated that plant extracts and/or secondary metabolites isolated from them reduce most ALI phenotypes in experimental animal models, including neutrophil recruitment to the lung, the production of pro-inflammatory cytokines and chemokines, edema, and vascular permeability. In this review, we summarized these studies and described the anti-inflammatory activity of various plant extracts, such as Ginkgo biloba and Punica granatum, and such secondary metabolites as epigallocatechin-3-gallate and ellagic acid. In addition, we highlight the medical potential of these extracts and plant-derived compounds for treating of ALI.
    Full-text · Article · Oct 2013
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