ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chang, C. K.
Right arrow Articles by LoCicero, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chang, C. K.
Right arrow Articles by LoCicero, J., III
Related Collections
Right arrow Lung - other

Ann Thorac Surg 2004;77:1222-1227
© 2004 The Society of Thoracic Surgeons

Original article: general thoracic

Overexpressed nuclear factor {kappa}B correlates with enhanced expression of interleukin-1ß and inducible nitric oxide synthase in aged murine lungs to endotoxic stress

Cheow K. Chang, PhDa, Joseph LoCicero, III, MDb*

a Department of Surgery, Finch University of Health Sciences/The Chicago Medical School at Mount Sinai Hospital Medical Center, Chicago, Illinois, USA
b Department of Surgery, University of South Alabama, Mobile, Alabama, USA

Accepted for publication September 11, 2003.

* Address reprint requests to Dr LoCicero, Department of Surgery, University of South Alabama, 2451 Fillingim St, MSTN 719, Mobile, AL 36617-2293, USA
e-mail: jlocicero{at}usouthal.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: Transcriptional regulation is a major determinant of interleukin-1ß (IL-1ß) protein synthesis. Nuclear factor {kappa}B (NF-{kappa}B) plays a central role in the regulation of IL-1ß and subsequent IL-1ß-dependent inflammatory processes. Previously, we observed in a murine endotoxic stress model a progressive increase with age in the amount of IL-1ß mRNA. We test the aging pulmonary response of NF-{kappa}B and NF-{kappa}B-dependent genes, IL-1ß, and inducible nitric oxide synthase (iNOS) in the same model.

METHODS: Young (2-month-old) and senescent (25-month-old) mice were given 0.5 mg/kg lipopolysaccharide (LPS) intraperitoneally. Lung and blood samples were harvested after 4 hours. IL-1ß production in blood samples and the expression levels of protein and mRNA of IL-1ß and iNOS in lung tissues were measured. NF-{kappa}B binding activity in lung tissues was also determined.

RESULTS: LPS induced higher levels of IL-1ß in the sera and lungs of senescent mice over young mice. Northern and Western blot analyses showed that mRNA and protein signals of IL-1ß and iNOS were significantly higher in old lungs than in young lungs. Electrophoretic mobility shift assay also showed that NF-{kappa}B activation was significantly higher in the older animals.

CONCLUSIONS: Our results suggest that elevated activation of NF-{kappa}B, at least in part, contributes to the dysregulated expression of IL-1ß and iNOS in the lungs of senescent animals. Thus increased expression of proinflammatory cytokines and inflammatory responsive genes in the lung may play a role in the increased susceptibility in aging animals to endotoxic stress.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Physiologic aging is associated with an altered response to stress and produces diminished immune function in individuals resulting from detrimentally altered functions of many organ systems [1, 2]. Pulmonary response to stress also declines with age in both animals and humans [3, 4] Lipopolysaccharide (LPS), an integral component derived from the outer membrane of gram-negative bacteria, is commonly used to produce local inflammation of the lungs as well as the systemic toxicity of gram-negative infection [5, 6]. Proinflammatory mediators including tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin (IL)-1ß are implicated in the mediation of host response to LPS [6]. These mediators in turn elicit a subsequent release of various genes including inducible nitric oxide (iNOS) which involves the inflammatory response [7]. Induction of iNOS by proinflammatory mediators is implicated for the excess production of NO in sepsis of animals, which contributes to the pathogenesis of septic shock and leads to multi-organ dysfunction including the lung [8, 9].

It is documented that the ability of animals to alleviate oxidative stress declines with age [10]. Reactive oxygen species serve as common intercellular signaling molecules that contribute to the activation of NF-{kappa}B during inflammation [11]. NF-{kappa}B is a crucial transcriptional factor required in activation of a variety of inflammatory cytokines including IL-1ß and inflammatory genes such as iNOS. NF-{kappa}B therefore plays an important role in regulation of IL-1ß and iNOS. In this study, we investigate whether aging plays a role in the pulmonary response of NF-{kappa}B activation and whether elevated NF-{kappa}B binding activity is associated with the dysregulation of IL-1ß and iNOS in the lung of senescent mice during endotoxic stress.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Animal model
The Animal Care and Use Committee at Mount Sinai Hospital Medical Center approved the experiment protocol. Young (2-month-old) and senescent (25-month-old) male B6C3F1 mice were obtained from the National Institute of Aging (Bethesda, MD). Animals were maintained at 20°C with free access to food and water. During the course of experiment, only water was provided ad libitum. Animals were injected intraperitoneally with LPS (E. coli serotype 026:B6, Difco, Detroit, MI) at a dosage of 0.5 mg/kg and control animals received only the vehicle normal saline. Six animals were used per treatment group. At 4 hours after LPS injection, lungs were removed and frozen in liquid nitrogen. Blood samples were also obtained through cardiac puncture for cytokine assays. Serum and lung samples were stored at −70°C.

Northern blot analysis
Total cellular RNA was extracted from lung tissue with guanidine isothiocyanate procedure as previously described [12]. RNA (10 µg) was electrophoresed on a 1% agarose-formaldehyde gel and transferred to a nylon membrane (PerkinElmer Life Sciences, Boston, MA). The RNA blots were hybridized at 42°C with a hybridization buffer containing 50% formamide, 1% SDS, 5% dextran sulfate, 1 mol/L NaCl, 100 µg/ml denatured salmon sperm, and radioactive labeled cDNA probe. cDNA fragments were [{alpha}-32P]-labeled by nick translation. The blots were washed and exposed to Roentgenogram film with an intensifying screen at −70°C. The relative radioactivities of the bands were quantified by densitometry and the mRNA bands were normalized to the corresponding glyceraldehyde-3-phosphate dehydrogenase (GAPDH) bands.

The following cDNA clones were used: murine iNOS (Dr. Cunningham of Brigham and Women's Hospital, Boston, MA); murine IL-1ß (Genetech, Inc., South San Francisco, CA); murine GAPDH cDNA (American Type Culture Collection, Rockville, MD).

Protein extraction
Lung tissues were homogenized in a buffer containing 0.3 mol/L sucrose, 3 mmol/L CaCl2, 2 mmol/L MgCl2, 0.5 mmol/L DTT, 0.1% nonidet P40, and 10 mmol/L Tris-HCl at pH 8.0. The homogenates were centrifuged at 5,000 x g and the supernatants were collected (cytosol extracts) and stored at −70°C. The pellets were resuspended in a lysing buffer (20 mmol/L Hepes, pH 7.9, 420 mmol/L NaCl, 2 mmol/L ethylenediaminetetruacetic acid (EDTA), 1.5 mmol/L MgCl2, 20% glycerol, 0.5 mmol/L phenylmethylsulfonyl fluoride, 0.5 mmol/L DTT). The lysates were centrifuged at 10,000 x g and the supernatants (nuclear extracts) were collected. The protein concentrations of the lysates and nuclear extracts were determined by the Bio-Rad protein assay (Bio-Rad Laboratories, Hercules, CA). Cytosol extracts were used for Western blot analysis and for iNOS, enzyme-linked immunosorbent assay (ELISA) was used for IL-1ß, and nuclear extracts were used for electrophoretic mobility shift assays (EMSAs).

Western blot analysis
Cytosol extracts (50 µg) were separated by 7% sodium dodecyl sulfate-polyacrylamide gel and electrotransferred onto a nitrocellulose membrane. The membrane was blocked with 5% nonfat milk in tris-buffered saline (TBST) (20 mmol/L Tris, pH 7.5, 500 mmol/L NaCl, 0.5% Tween 20) at room temperature for 1 hour. The membrane was then incubated with a rabbit antimouse iNOS polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA) for 2 hours. The membrane was washed in TBST and was incubated with horseradish peroxidase labeled goat antirabbit immunoglobulin G (IgG). Immunoreactive proteins were detected by enhanced chemiluminescence. The intensity of autoradiographic bands was quantified by densitometry.

EMSA
A double-stranded oligonucleotide corresponding to the NF-{kappa}B consensus sequence (5'-AGTTGAGGGGACTTTCCCAGGC-3') was labeled with [{gamma}-32P]ATP using T4 polynucleotide kinase. The DNA binding reaction was performed at room temperature in a mixture containing 4 µg of nuclear protein, 1 µg of poly (dIdC) and 100,000 cycles per minute (cpm) labeled NF-{kappa}B probe for 30 minutes. Competitive and supershift assays were performed to confirm the specificity of the NF-{kappa}B signal band in EMSA. For competitive assays, a 50-fold molar excess of cold NF-{kappa}B was added 10 minutes before the addition of radiolabeled probe. For supershift assay analysis 2 µg of antibody specific to p50 and p65 subunits of NF-{kappa}B was preincubated in the binding reaction for 10 minutes before the addition of radiolabeled probe. Binding reactions were resolved on a 7% polyacrylamide gel in 25 mmol/L Tris-HCl, 0.34 mol/L glycine, and 1 mmol/L EDTA. Gel was exposed to Roentgenogram film with an intensifying screen at −70°C. Gel shift signals were quantified by densitometry.

Cytokine assay
IL-1ß production in the serum and lung was determined by a commercial available ELISA kit (Endogen Inc., Boston, MA) and is expressed as pg/ml of serum and pg/mg of protein in cytosol extracts respectively.

Statistical analysis
Results are expressed as means ± standard deviation (SD) of n = 6 animals per group. Statistical comparisons were performed by using one-way analysis of variance (ANOVA) followed by Newman–Keuls test. Statistical significance is set at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Serum IL-1ß production in response to LPS challenge
Serum IL-1ß level was elevated significantly in both young and senescent mice treated with LPS compared with their respective controls receiving normal saline only (Figure 1). However the level of LPS-induced IL-1ß was 2.6-fold higher in senescent mice than in young mice. Very low constitutive IL-1ß was detected in the young and senescent control animals. This finding suggests that aging is associated with enhanced production of circulating IL-1ß in senescent mice during endotoxic stress.



View larger version (15K):
[in this window]
[in a new window]
  		Fig 1. Serum level of interleukin-1ß (IL-1ß) production in controls and lipopolysaccharide (LPS) treated young and senescent mice. Results are expressed as mean ± standard deviation of n = 6 animals per group. *p < 0.05 versus controls (C) of young and senescent mice; #p < 0.05 versus LPS treated young mice.

 
IL-1ß and iNOS gene transcription in septic lungs
The mRNA levels of lung IL-1ß and iNOS were significantly elevated in both young and senescent mice in comparison with their respective controls at 4 hours after LPS injection (Figure 2). The expression of IL-1ß and iNOS mRNA was 3.0-fold and 2.6-fold higher, respectively, in old lungs than in young lungs. These results demonstrate that aging alters the induction pattern of IL-1ß and iNOS at the transcriptional level in the lung of senescent mice during endotoxic stress.



View larger version (21K):
[in this window]
[in a new window]
  		Fig 2. Northern blot analysis of total RNA of representative lung samples from controls and lipopolysaccharide (LPS) treated young and senescent mice. (A) Autoradiogram of Northern blots. (B & C) The bar graphs show the relative intensities interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) mRNA signals which were normalized with the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA signal. Results are expressed as mean ± standard deviation of n = 6 animals per group. *p < 0.05 versus controls (C) of young and senescent mice; # p < 0.05 versus LPS treated young mice.

 
IL-1ß and iNOS protein expression in septic lungs
LPS-induced IL-1ß protein measured by ELISA was 3.0-fold higher in old lungs than in young lungs (Figure 3). Very low levels of constitutive IL-1ß were detected in control lungs of young and senescent mice. Western blot analysis showed that iNOS protein with a putative molecular weight of 130 kDa was significantly induced in both young and old lungs after LPS treatment (Figure 4). There was no significant amount of iNOS protein detected in lung tissues of control mice. Expression of iNOS was 1.7-fold higher in senescent lungs than in young lungs after LPS treatment. These results indicate that aging alters IL-1ß and iNOS at the posttranscriptional level in senescent lungs during endotoxic stress.



View larger version (16K):
[in this window]
[in a new window]
  		Fig 3. Interleukin-1ß (IL-1ß) production from lungs of controls and lipopolysaccharide (LPS) treated young and senescent mice. Results are expressed as mean ± SD of n = 6 animals per group. *p < 0.05 versus controls (C) of young and senescent mice; # p < 0.05 versus LPS treated young mice.

 


View larger version (23K):
[in this window]
[in a new window]
  		Fig 4. Western blot analysis of representative lung tissues from controls and lipopolysaccharide (LPS) treated young and senescent mice. (A) Autoradiogram of the Western blot. (B) The bar graph presents relative inducible nitric oxide synthase (iNOS) protein levels. Results are expressed as mean ± standard deviation of n = 6 animals per group. *p < 0.05 versus controls (C) of young and senescent mice; #p < 0.05 versus LPS treated young mice.

 
LPS-induced in vivo NF-{kappa}B activation in young and senescent lungs
EMSA showed a low level of constitutive NF-{kappa}B activation in lung nuclear extracts of young and senescent control mice (Figure 5). LPS treatment induced NF-{kappa}B activation significantly in young and senescent mice in comparison with control animals receiving only normal saline. The activation of NF-{kappa}B was 1.5-fold higher in old lungs in comparison with that in young lungs after LPS treatment. The composition of NF-{kappa}B subunits activated by LPS in lung tissues was analyzed using specific antibodies to p50 and p65 subunits in a supershift assay. Supershifted subunits were observed in the presence of antibodies to p50 and p65 suggesting these two subunits were activated in the lungs of senescent mice (Figure 5). The NF-{kappa}B binding in lung nuclear extract was completely inhibited by excess cold NF-{kappa}B which demonstrated the sequence specificity of the binding reaction. This finding suggests that enhanced NF-{kappa}B activation in the lung correlates directly with advancing age during endotoxic stress.



View larger version (23K):
[in this window]
[in a new window]
  		Fig 5. NF-{kappa}B activation from lung tissues of representative animals from controls and lipopolysaccharide (LPS) treated animals. (A) Nuclear factor-{kappa}B (NF-{kappa}B) binding activity was measured in nuclear extracts from the lung of control young mice (lane 1), LPS treated young mice (lane 2), control senescent mice (lane 3), and LPS treated senescent mice (lane 4). Specificity of NF-{kappa}B was verified by competition reaction of nuclear extract from LPS treated senescent mice with excess unlabeled NF-{kappa}B (lane 5) and supershift assays in the presence of antibodies specific to p50 (lane 6) and p65 (lane 7). Lane 8 shows the probe without nuclear extract. (B) The bar graph presents relative NF-{kappa}B activation. Results are expressed as mean ± standard deviation of n = 6 animals per group. *p < 0.05 versus controls (C) of young and senescent mice; #p < 0.05 versus LPS treated young mice.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
In a previous study of lung inflammation in young, mature, and senescent mice, we observed a progressive increase in the amount of IL-1ß mRNA expressed with increasing age after LPS treatment [13]. Thus the physiologic function of IL-1ß mRNA and IL-1ß regulation during whole body stress and infection is very important. NF-{kappa}B is an important transcriptional factor required in activating a variety of inflammatory cytokines such as IL-1ß and inflammatory responsive genes like iNOS. This study investigates whether aging plays a role in the pulmonary response of NF-{kappa}B activation and whether elevation in NF-{kappa}B binding activity is associated with the dysregulation of IL-1ß and iNOS in the lung of senescent mice during endotoxic stress.

As the major endotoxin in gram-negative infection, LPS can stimulate the expression of a variety of cytokines that orchestrate inflammation. IL-1ß is one of the most important and well-studied LPS-induced proinflammatory cytokines. IL-1ß is produced by resident lung and circulating macrophages. Locally accentuated activation of IL-1ß plays an important role in inflammation and the regulation of various inflammatory responsive genes including iNOS [14]. Our results showed that the serum IL-1ß level was significantly higher in senescent mice than in young mice after LPS treatment. This is consistent with studies reporting higher in vitro production of IL-1ß by blood mononuclear cells of old people than that of young people [15, 16]. Thus the increased production of proinflammatory cytokines in older subjects may play a role in the pathophysiology of some diseases associated with aging. Our results also illustrated that the expression levels of LPS-induced IL-1ß mRNA and protein were significantly higher in old lungs than in young lungs. Others have noted that the level of IL-1ß mRNA in hyperoxic lungs of adult mice and LPS-stimulated alveolar macrophages from adult rabbits is elevated when compared with that in newborn animals [17, 18]. Taken together, our results suggest that the aging enhances the in vivo production of IL-1ß in the serum and lung of senescent mice.

The ability of animals to effectively contend with oxidative stress declines with age [10]. Reactive oxygen species lead to phosphorylation, ubiquitination, and proteolysis of I{kappa}B which liberates NF-{kappa}B [11]. Our study illustrates that LPS-induced NF-{kappa}B activation was elevated significantly in old lungs than in young lungs. Studies employing deletion and mutation of the iNOS promoter region revealed that the regulation of murine iNOS gene might require the coexistence of two NF-{kappa}B sites and other responsive elements in the 5' flanking region [19]. NF-{kappa}B activation is a crucial in vivo regulatory step in mediating LPS-induced iNOS expression in the lung of a rat model of septic shock [5]. Our results show that there is a direct correlation between elevation of NF-{kappa}B activation and increased iNOS mRNA in old lungs. Taken together, the enhanced responsiveness of lung NF-{kappa}B activation may, at least in part, play a role in regulating iNOS at the transcriptional level in the senescent mice during endotoxic stress.

The induction of iNOS by proinflammatory cytokines such as TNF-{alpha} and IL-1ß is responsible for the excess production of NO leading to the development of shock in animal models [5, 20]. Inhibition of iNOS expression in the lung by therapeutic agents prevents endotoxemia in LPS-induced multiple organ dysfunction syndrome in rats [21, 22]. Our results indicate that increased expression of lung iNOS correlates with IL-1ß expression in senescent mice during endotoxic stress. This finding suggests that LPS-induced iNOS may contribute to the increased risk of pathologic processes associated with aging.

Our results indicate that elevated activation of NF-{kappa}B, at least in part, contributes to the dysregulated expression of IL-1ß and iNOS in the lung of senescent animals. These findings are consistent with the notion that NF-{kappa}B is a key transcriptional modulator of IL-1ß and iNOS. Thus increased expression of proinflammatory cytokines and inflammatory responsive genes in the lung may play a role in the increased susceptibility in senescent animals to endotoxic stress.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Tateda K., Matsumoto T., Miyazaki S., Yamaguchi K. Lipopolysaccharide-induced lethality and cytokine production in aged mice. Infect Immun 1996;64:769-774.[Abstract]
  2. Chorinchath B.B., Kong L.-Y., Mao L., McCallum R.E. Age-associated differences in TNF-{alpha} and nitric oxide production in endotoxic mice. J Immunol 1996;156:1525-1530.[Abstract]
  3. Martin T.R., Ruzinski J.T., Wilson C.B., Skerrett S.J. Effect of endotoxin in the lungs of neonatal rats: age-dependent impairment of the inflammatory response. J Infect Dis 1995;171:134-144.[Medline]
  4. Meyer K.C., Ershler W., Rosenthal N.S., Lu X.-G., Peterson K. Immune dysregulation in the aging human lung. Am J Respir Crit Care Med 1996;153:1072-1079.[Abstract]
  5. Liu S.F., Ye X., Malik A.B. In vivo inhibition of nuclear factor-{kappa}B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J Immunol 1997;159:3976-3983.[Abstract]
  6. Flohe S., Dominguez Fernandez E., Ackermann M., Hirsch J., Borgermann J., Schade F.U. Endotoxin tolerance in rats: expression of TNF-{alpha}, IL-6, IL-10, VCAM-1, and HSP 70 in lung and liver during endotoxin shock. Cytokine 1999;11:796-804.[Medline]
  7. Asano K., Chee C.B.E., Gaston B., Lilly C.M., Gerard C., Drazen J.M., Stamler J.S. Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci USA 1994;91:10089-10093.[Abstract/Free Full Text]
  8. Walley K.R., McDonald T.E., Higashimoto Y., Hayashi S. Modulation of proinflammatory cytokine by nitric oxide in murine acute lung injury. Am J Respir Crit Care Med 1999;160:698-704.[Abstract/Free Full Text]
  9. Numata M., Suzuki S., Miyazawa N., Miyashita A., Nagashima Y., Inoue S., Kaneko T., Okubo T. Inhibition of inducible nitric oxide synthase prevents LPS-induced acute lung injury in dogs. J Immunol 1998;160:3031-3037.[Abstract/Free Full Text]
  10. Yan Z.-Q., Sirsjo A., Bochaton M.-L., Gabbiani G., Hansson G. Augmented expression of inducible NO synthase in vascular smooth muscle cells during aging is associated with enhanced NF-{kappa}B activation. Arterioscler Thromb Vasc Biol 1999;19:2854-2862.[Abstract/Free Full Text]
  11. Baldwin A.S., Jr The NF-{kappa}B and I{kappa}B proteins: new discoveries and insights. Annu Rev Immunol 1996;14:649-683.[Medline]
  12. Chirgwin J.M., Przybyla A.E., MacDonald R.J., Rutter W.J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 1979;18:5294-5299.[Medline]
  13. LoCicero J., III, Xu X., Zhang L. Heat shock protein suppresses the senescent lung cytokine response to acute endotoxemia. Ann Thorac Surg 1999;68:1150-1153.[Abstract/Free Full Text]
  14. Kunz D., Walker G., Eberhardt W., Pfeilschifter J. Molecular mechanisms of dexamethane inhibition of nitric oxide synthase expression in interleukin 1ß-stimulated mesangial cells: Evidence for the involvement of transcriptional and posttranscriptional regulation. Proc Natl Acad Sci USA 1996;93:255-259.[Abstract/Free Full Text]
  15. Riancho J.A., Zarreabeitia M.T., Amado J.A., Olmos J.M., Gonzalez-Macisa J. Age-related differences in cytokine secretion. Gerontology 1994;40:8-12.[Medline]
  16. Fagiolo U., Cossarizza A., Scala E., Fanales-Balasio E., Ortolani C., Cozzi E., Monti D., Franceschi C., Paganelli R. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 1993;23:2375-2378.[Medline]
  17. Johnston C.J., Wright T.W., Reed C.K., Finkelstein J.N. Comparison of adult and newborn pulmonary cytokine mRNA expression after hyperoxia. Exp Lung Res 1997;23:537-552.[Medline]
  18. Rozycki H.J. Elevated production of interleukin-1ß from alveolar macrophages isolated from newborn rabbits. Biol Neonate 1994;66:93-99.[Medline]
  19. Zhang H., Chen X., Teng X., Snead C., Catravas J.D. Molecular cloning and analysis of the rat inducible nitric oxide synthase gene promoter in aortic smooth muscle cells. Biochem Pharmacol 1998;55:1873-1880.[Medline]
  20. Hierholzer C., Menezes J.M., Ungeheuer A., Billar T.R., Tweardy D.J., Harbrecht B.G. A nitric oxide scavenger protects against pulmonary inflammation following hemorrhagic shock. Shock 2002;17:98-103.[Medline]
  21. Crespo E, Macias M, Pozo D, Escames G, Martin M, Vives F, Guerrere JM, Acuna- Castroviejo. Melatin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. Fed Am Soc Exp Biol J 1999;13:1537–46
  22. Arkovitz M.S., Wispe J.R., Garcia V.F., Szabo C. Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia. J Pediatr Surg 1996;31:1009-1015.[Medline]



This article has been cited by other articles:


Home page
 J Gerontol A Biol Sci Med SciHome page
W. Song, H.-B. Kwak, J.-H. Kim, and J. M. Lawler
Exercise Training Modulates the Nitric Oxide Synthase Profile in Skeletal Muscle From Old Rats
J Gerontol A Biol Sci Med Sci, May 1, 2009; 64A(5): 540 - 549.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Billiet, C. Furman, G. Larigauderie, C. Copin, K. Brand, J.-C. Fruchart, and M. Rouis
Extracellular Human Thioredoxin-1 Inhibits Lipopolysaccharide-induced Interleukin-1{beta} Expression in Human Monocyte-derived Macrophages
J. Biol. Chem., December 2, 2005; 280(48): 40310 - 40318.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. M. Littler, C. A. Wehling, M. J. Wick, K. A. Fagan, C. D. Cool, R. O. Messing, and E. C. Dempsey
Divergent contractile and structural responses of the murine PKC-{epsilon} null pulmonary circulation to chronic hypoxia
Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L1083 - L1093.
[Abstract] [Full Text] [PDF]

Home page
 Journals of Gerontology Series A: Biological Sciences and Medical SciencesHome page
A. P. S. Hikim, Y. Vera, D. Vernet, M. Castanares, M. Diaz-Romero, M. Ferrini, R. S. Swerdloff, N. F. Gonzalez-Cadavid, and C. Wang
Involvement of Nitric Oxide-Mediated Intrinsic Pathway Signaling in Age-Related Increase in Germ Cell Apoptosis in Male Brown-Norway Rats
J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2005; 60(6): 702 - 708.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
R. A. Kowluru and S. Odenbach
Role of Interleukin-1{beta} in the Development of Retinopathy in Rats: Effect of Antioxidants
Invest. Ophthalmol. Vis. Sci., November 1, 2004; 45(11): 4161 - 4166.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chang, C. K.
Right arrow Articles by LoCicero, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chang, C. K.
Right arrow Articles by LoCicero, J., III
Related Collections
Right arrow Lung - other

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS