UMLS:C0004135 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that losartan, a selective antagonist of AT1 receptors for angiotensin II (AII), strongly suppresses the activation of neutrophils by N-formylmethionyl-leucyl-phenylalanine (fMLP) through a mechanism that does not involve inhibition of AT1 receptors. Herein, we analyze whether losartan would prevent the development of the acute respiratory distress syndrome (ARDS) triggered by lung bacterial infection. We found that losartan (0.2-200 microg/kg/min) delays the onset of ARDS in Wistar rats challenged by i.t. instillation of Bordetella bronchiseptica. Although this effect was associated with a significant inhibition of lung-neutrophil recruitment, lung bacterial clearance was not impaired but rather, it was significantly improved. We also found that another nonpeptide AT1 receptor blocker, irbesartan, exerted similar effects to losartan, i.e., it was also able to inhibit neutrophil activation by fMLP and to delay the onset of ARDS in B. bronchiseptica-challenged rats. Neither the inhibitor of angiotensin-converting enzyme captopril, nor the nonselective peptide inhibitor of AII receptors saralasin reproduced these effects. Our data are consistent with the possibility that nonpeptide AT1 receptor blockers delay the onset of ARDS triggered by bacterial infection through a mechanism dependent, at least in part, on their ability to prevent neutrophil activation by N-formyl-peptides.
...
PMID:Nonpeptide antagonists of AT1 receptor for angiotensin II delay the onset of acute respiratory distress syndrome. 1223 31

The methylxanthine drug Pentoxifylline is reviewed for new properties which have emerged only relatively recently and for which clinical applications can be expected. After a summary on the established systemic effects of Pentoxifylline on the microcirculation and reduction of tumour anoxia, the role of the drug in the treatment of vasoocclusive disorders, cerebral ischemia, infectious diseases, septic shock and acute respiratory distress, the review focuses on another level of drug action which is based on in vitro observations in a variety of cell lines. Pentoxifylline and the related drug Caffeine are known radiosensitizers especially in p53 mutant cells. The explanation that the drug abrogates the G2 block and shortens repair in G2 by promoting early entry into mitosis is not anymore tenable because enhancement of radiotoxicity requires presence of the drug during irradiation and fails when the drug is added after irradiation at the G2 maximum. Repair assays by measurement of recovery ratios and by delayed plating experiments indeed strongly suggested a role in repair which is now confirmed for Pentoxifylline by constant field gel electrophoresis (CFGE) measurements and for Pentoxifylline and for Caffeine by use of a variety of repair mutants. The picture now emerging shows that Caffeine and Pentoxifylline inhibit homologous recombination by targeting members of the PIK kinase family (ATM and ATR) which facilitate repair in G2. Pentoxifylline induced repair inhibition between irradiation dose fractions to counter interfraction repair has been successfully applied in a model for stereotactic surgery. Another realistic avenue of application of Pentoxifylline in tumour therapy comes from experiments which show that repair events in G2 can be targeted directly by addition of cytotoxic drugs and Pentoxifylline at the G2 maximum. Under these conditions massive dose enhancement factors of up to 80 have been observed suggesting that it may be possible to realise dramatic improvements to tumour growth control in the clinic.
...
PMID:Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives. 1459 74

Morbidity and mortality rates of ARDS (acute respiratory distress syndrome) are high in patients with a history of chronic alcohol abuse. In addition to susceptibility to lung infection, alteration of local cellular functions in the lung has recently been proposed as a new mechanism of exacerbation of ARDS in patients with a history of chronic alcohol abuse. Clinical studies and studies using animal experiments have shown that a decrease in lung glutathione levels is associated with exacerbation of ARDS in chronic alcohol abuse. In the alcoholic lung, depletion of glutathione increases oxidative stress derived from activated neutrophils, resulting in decreased surfactant production, apoptosis and increased permeability of alveolar epithelial type II cells, in which TGF-beta1 may be involved. Acetoaldehyde has been suggested to be involved in the mechanism of exacerbation of ARDS by inducing lung remodeling through stimulation of fibronectin expression following nicotinic acetylcholine receptor stimulation and CREB activation in chronic alcohol abuse. More recently, antagonists of angiotensin II type-1 receptor (AT1 receptor) have been shown to prevent glutathione depletion, increase in TGF-beta1 expression and lung edema in endotoxemic rats with chronic alcohol administration. On the other hand, macrophage-derived prostaglandin E2 plays a protective role at an initial phase of ARDS by inhibiting cytokine production by macrophages and extravascular invasion of activated neutrophils. Our recent studies have shown that LPS-induced COX-2 expression and subsequent prostaglandin E2 production in rat alveolar macrophages are inhibited by ethanol incubation in vitro and ethanol administration in vivo. Only a decade has passed since alcohol abuse was demonstrated to be associated with increased mortality of ARDS and future studies are needed to clarify the mechanism underlying alcohol-induced exacerbation of ARDS.
...
PMID:[Alcohol abuse as a risk factor for ARDS]. 1717 45

Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated. We have investigated the effect of hyperoxia on DNA damage signaling and show that hyperoxia is a unique stress that activates the ataxia telangiectasia mutant (ATM)- and Rad3-related protein kinase (ATR)-dependent p53 phosphorylations (Ser6, -15, -37, and -392), phosphorylation of histone H2AX (Ser139), and phosphorylation of checkpoint kinase 1 (Chk1). In addition, we show that phosphorylation of p53 (Ser6) and histone H2AX (Ser139) depend on both ATM and ATR. We demonstrate that ATR activation precedes ATM activation in hyperoxia. Finally, we show that ATR is required for ATM activation in hyperoxia. Taken together, we report that ATR is the major DNA damage signal transducer in hyperoxia that activates ATM.
...
PMID:Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation. 1834 16

Lack of specific and efficient therapy leads to the high mortality rate of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Losartan is a potent pharmaceutical drug for ALI/ARDS. However, the protective effects and mechanisms of losartan remain incompletely known. This study evaluates the effects of losartan on ALI/ARDS and further investigates the possible mechanisms of these protective effects. Mice received i.p. injections of the AT1 inhibitor losartan (15 mg/kg), or control vehicle, half hour after cecal ligation and puncture (CLP). Plasma TNF-alpha, IL-1beta, and IL-6 cytokines were assayed 6 h after CLP. Blood gas, wet/dry lung weight ratio, lung tissue histology for occurrence of ALI/ARDS, and survival were examined. Lastly, nuclear factor kappaB (NF-kappaB) activations, IkappaB-alpha degradations, phosphorylations of p38 MAPK, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase expressions were evaluated in lung tissue. Losartan treatment significantly attenuated TNF-alpha, IL-6, and IL-1beta 6 h after CLP. Furthermore, losartan prevented blood gas and histopathologic appearance of ALI/ARDS after sepsis and significantly improved survival. Finally, losartan given after sepsis led to inhibition of lung tissue NF-kappaB activation (P < 0.01 vs. CLP group), attenuated degradation of IkappaB-alpha, and inhibited phosphorylation of p38MAPK, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase, pathways critical for cytokine release. These data reveal that losartan exerts a protective effect on ALI/ARDS, and this protective effect may be dependent, at least in part, on NF-kappaB and MAPK mechanisms.
...
PMID:Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases. 1882 41

Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4^COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.
...
PMID:Transcription factor Etv5 is essential for the maintenance of alveolar type II cells. 2835 80

BACKGROUND The body of literature on oral motor and swallowing disorders in patients with ataxia telangiectasia (AT) is limited. CASE REPORT The purpose of this study was to characterize oral motor and swallowing disorders in two siblings with AT, based on oral motor and swallowing assessments. Specific procedures were applied for oral motor and swallowing assessments and both patients underwent videofluoroscopy (VFS). Case 1 presented vocal instability, change in postural control during feeding; food retention in oral cavity; slower oral transit time; and multiple swallowing (signs for solid and liquid). Case 2 presented parted lips at rest and reduced muscle strength; reduced strength and mobility of the tongue; vocal weakness and instability; reduced speech precision and intelligibility; decreased intonation pattern; food retention in oral cavity during feeding; slower oral transit time; multiple swallowing (signs for solid and liquid); poor bolus ejection; incoordination and difficulty in controlling the sips of water taken from the cup; altered cervical auscultation after swallowing and respiratory distress (liquid and puree). For both patients VFS results revealed laryngeal penetration for liquid. CONCLUSIONS Although the literature describes the occurrence of dysarthria and swallowing disorders in patients with AT, little attention has been given to describing which oral motor deficits are responsible for these disorders. Early identification of swallowing alterations and rehabilitation could decrease the risk of aspiration pneumonia. Future studies are necessary in order to investigate the deterioration process of swallowing in AT and the influence of rehabilitation in maintaining functional health.
...
PMID:Ataxia Telangiectasia in Siblings: Oral Motor and Swallowing Characterization. 2869 41