Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Davis, Ian C.; Lazarowski, Eduardo R.; Hickman-Davis, Judy M.; Fortenberry, James A.; Chen, Fu Ping; Zhao, Xiaodong; Sorscher, Eric J.; Graves, Lee M.; Sullender, Wayne M.; Matalon, Sadis

doi:10.1164/rccm.200508-1200oc

Cited by 55 publications

(70 citation statements)

References 52 publications

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“…Constitutive BAL IL-18 concentration was significantly higher in Nrf 2 2/2 mice than in Nrf 2 1/1 mice, and IL-18 was significantly more elevated by RSV in Nrf 2 2/2 mice than in Nrf 2 1/1 mice after 5 days. BAL concentrations of the Th1 cytokine IFN-g in Nrf 2 1/1 mice were not significantly increased relative to controls until 7 days after RSV infection as shown in previous kinetic studies of murine RSV models (7,34), but lung IFN-g was not significantly increased at any time in Nrf 2 2/2 mice. Among BAL Th2 cytokines, IL-10 was not significantly changed in Nrf 2 1/1 mice but was significantly elevated in Nrf 2 2/ 2 mice at 7 days.…”

Section: Differential Pulmonary Cytokine Profiles After Rsv Infectionsupporting

confidence: 59%

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

Cho

Imani

Miller-DeGraff

et al. 2009

Am J Respir Crit Care Med

171

170

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Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf 2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction. Objectives: The current study was designed to determine the role of Nrf 2-mediated cytoprotective mechanisms in murine airway RSV disease. Methods: Nrf 2-deficient (Nrf 2 2/2 ) and wild-type (Nrf 2 1/1 ) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf 2 1/1 and Nrf 2 2/2 mice were treated orally with sulforaphane (an Nrf 2-ARE inducer) or phosphate-buffered saline before RSV infection. Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf 2 2/2 mice than in Nrf 2 1/1 mice. Compared with Nrf 2 1/1 mice, significantly attenuated viral clearance and IFN-g, body weight loss, heightened protein/ lipid oxidation, and AP-1/NF-kB activity along with suppressed antioxidant induction was found in Nrf 2 2/2 mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf 2 1/1 but not in Nrf 2 2/2 mice. Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf 2-ARE pathway in host defense against RSV.

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Section: Differential Pulmonary Cytokine Profiles After Rsv Infectionsupporting

confidence: 59%

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

Cho

Imani

Miller-DeGraff

et al. 2009

Am J Respir Crit Care Med

171

170

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“…A standard curve was prepared by assaying known concentrations of bovine serum albumin in 0.9% NaCl. AFC values were calculated as described before (24,32). In some cases mice were anesthetized with isoflurane 15 min post-Cl 2 exposure, and 100 l of saline containing either trypsin (5 M) or vehicle were instilled dropwise in their nostrils.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Lung Fluid Clearance and Epithelial Na+ Channels by Chlorine, Hypochlorous Acid, and Chloramines

Song¹,

Wei²,

Zhou³

et al. 2010

Journal of Biological Chemistry

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We investigated the mechanisms by which chlorine (Cl 2 ) and its reactive byproducts inhibit Na ؉ -dependent alveolar fluid clearance (AFC) in vivo and the activity of amiloridesensitive epithelial Na ؉ channels (ENaC) by measuring AFC in mice exposed to Cl 2 (0 -500 ppm for 30 min) and Na ؉ and amiloride-sensitive currents (I Na and I amil , respectively) across Xenopus oocytes expressing human ␣-, ␤-, and ␥-ENaC incubated with HOCl (1-2000 M). Both Cl 2 and HOCl-derived products decreased AFC in mice and whole cell and single channel I Na in a dose-dependent manner; these effects were counteracted by serine proteases. Mass spectrometry analysis of the oocyte recording medium identified organic chloramines formed by the interaction of HOCl with HEPES (used as an extracellular buffer). In addition, chloramines formed by the interaction of HOCl with taurine or glycine decreased I Na in a similar fashion. Preincubation of oocytes with serine proteases prevented the decrease of I Na by HOCl, whereas perfusion of oocytes with a synthetic 51-mer peptide corresponding to the putative furin and plasmin cleaving segment in the ␥-ENaC subunit restored the ability of HOCl to inhibit I Na . Finally, I Na of oocytes expressing wild type ␣-and ␥-ENaC and a mutant form of ␤ENaC (S520K), known to result in ENaC channels locked in the open position, were not altered by HOCl. We concluded that HOCl and its reactive intermediates (such as organic chloramines) inhibit ENaC by affecting channel gating, which could be relieved by proteases cleavage.The balance of fluid covering the respiratory and alveolar epithelia is determined in part by the ability of these cells to transport sodium (Na ϩ ) and chloride (Cl Ϫ ) ions in a vectorial fashion. Active Na ϩ reabsorption across lung epithelia requires the coordinated entry of Na ϩ ions through cation-and Na ϩ -selective amiloride-sensitive channels (ENaC) 5 located at the apical membranes, their extrusion across the basolateral membranes by the electrogenic Na ϩ -K ϩ -ATPase, and the passive movement of K ϩ ions through basolateral K ϩ channels. The entry of Na ϩ ions through apical pathways is thought to be the rate-limiting step in this process (1-3). To preserve neutrality, Cl Ϫ ions follow Na ϩ ions both through transcellular and paracellular pathways (4, 5). The coordinated movement of Na ϩ and Cl Ϫ ions creates an oncotic gradient favoring the absorption of alveolar fluid.Injury to either apical or basolateral pathways by partially reduced intermediates may lead to impairment of fluid reabsorption, which in turn may result in pulmonary edema, hypoxemia, and eventually death from respiratory failure (6 -9). One such specie is hypochlorous acid (HOCl) 6 , which may be generated either endogenously or exogenously. Millimolar concentrations of HOCl may be generated by activated neutrophils and eosinophils by the catalytic actions of neutrophil-and eosinophil-derived myeloperoxidases on chloride (Cl Ϫ ) and hydrogen peroxide (H 2 O 2 ) in close proximity of the apical and basolatera...

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“…Before such instruments were available, pediatric pulse oximetry devices were commonly used. However, the sensors in these analyzers were unable to detect the high-frequency pulsatile nature of arterial blood flow in mice and therefore gave an artificially low reading reflecting the average of arterial and venous blood oxygenation levels (Davis et al 2006). Generally, SpO 2 values of less than 90% are viewed as hypoxemic; however, rigid cutoff values do not exist for either animals or humans, so decisions regarding the relevance of decreased readings are subject to interpretation.…”

Section: Main Feature: Measurements Of Physiological Dysfunction Hypomentioning

confidence: 99%

Mouse Models of Acute Respiratory Distress Syndrome

Aeffner¹,

2015

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Acute respiratory distress syndrome (ARDS) is a severe pulmonary reaction requiring hospitalization, which is incited by many causes, including bacterial and viral pneumonia as well as near drowning, aspiration of gastric contents, pancreatitis, intravenous drug use, and abdominal trauma. In humans, ARDS is very well defined by a list of clinical parameters. However, until recently no consensus was available regarding the criteria of ARDS that should be evident in an experimental animal model. This lack was rectified by a 2011 workshop report by the American Thoracic Society, which defined the main features proposed to delineate the presence of ARDS in laboratory animals. These should include histological changes in parenchymal tissue, altered integrity of the alveolar capillary barrier, inflammation, and abnormal pulmonary function. Murine ARDS models typically are defined by such features as pulmonary edema and leukocyte infiltration in cytological preparations of bronchoalveolar lavage fluid and/or lung sections. Common pathophysiological indicators of ARDS in mice include impaired pulmonary gas exchange and histological evidence of inflammatory infiltrates into the lung. Thus, morphological endpoints remain a vital component of data sets assembled from animal ARDS models.

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Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Cited by 55 publications

References 52 publications

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease

Inhibition of Lung Fluid Clearance and Epithelial Na+ Channels by Chlorine, Hypochlorous Acid, and Chloramines

Mouse Models of Acute Respiratory Distress Syndrome

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