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CUTTING EDGE |
*
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; and
Laboratory of Biomedical Science, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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, and
macrophage-inflammatory protein-2. In endotoxin-induced acute lung
inflammation, administration of anti-HMG-1 Abs either before or
after endotoxin exposure decreased the migration of neutrophils to the
lungs as well as lung edema. These protective effects of anti-HMG-1
were specific, because pulmonary levels of IL-1ß, TNF-, or
macrophage-inflammatory protein-2 were not decreased after therapy with
anti-HMG-1. Together, these findings indicate that HMG-1 is a
distal mediator of acute inflammatory lung
injury. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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150,000 patients per year in
the U.S., with recent mortality rates being >30% (1, 2, 3).
At present, there is no effective treatment. Acute lung injury
often develops after the onset of injury or severe infection
(4, 5, 6). The pathogenesis involves increased production of
inflammatory mediators, such as TNF- and IL-1ß, and is
characterized histologically by accumulation of large numbers of
neutrophils and the development of interstitial edema (1, 2, 3, 6). High mobility group protein-1 (HMG-1)3 is a highly conserved protein with >95% amino acid identity between rodents and humans (7, 8). HMG-1 was initially characterized as a nonhistone nuclear protein that binds to the narrow minor groove of AT sequence-rich B form DNA. It has been implicated in the regulation of gene transcription and in stabilizing nucleosome formation (7, 8, 9, 10, 11). HMG-1 also is present in a membrane associated form, termed amphoterin, that mediates neurite outgrowth (8, 12). Amphoterin can interact with macrophage cell surface receptors for advanced glycation end products to enhance expression of tissue-type plasminogen activator (12, 13, 14). HMG-1 was recently identified as a late mediator of endotoxin lethality (15). Circulating levels of HMG-1 rose after the administration of endotoxin, and injection of HMG-1 itself was lethal. Abs to HMG-1 attenuated mortality associated with endotoxemia, even when the Abs were administered 2 h after the onset of endotoxemia, when the TNF peak had already occurred (15). Moreover, in patients with severe infection, increased serum HMG-1 levels correlated with nonsurvival (15).
Because endotoxin and proinflammatory cytokine release is important in
the mediation of acute lung injury (1, 2, 3, 4, 5, 6), we reasoned
that HMG-1 might also be involved in the development and progression of
this entity. The present experiments show that HMG-1 itself can cause
an acute pulmonary inflammatory response, manifested by neutrophil
accumulation, interstitial edema, and increased production of
proinflammatory cytokines in the lungs. Anti-HMG-1 Abs attenuated
endotoxin-induced lung injury, but not the early release of TNF- and
IL-1ß, indicating that HMG-1 is a late mediator of endotoxin-induced
acute lung injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Male C3H/HeJ mice, 8–12 wk of age, were purchased from The Jackson Laboratory (Bar Harbor, ME), and BALB/c mice, 8–12 wk of age, were purchased from Harlan Sprague Dawley (Indianapolis, IN). The mice were kept on a 12-h light/dark cycle with free access to food and water. All experiments were conducted in accordance with institutional review board-approved protocols.
Model of endotoxin exposure and anti-HMG-1 treatment
Methoxyfluorane-anesthetized BALB/c mice received 5 µg
Escherichia coli O111:B4 endotoxin (Sigma, St. Louis, MO)
intratracheally (i.t.) in 50 µl PBS. Control mice were given 50 µl
PBS i.t. without LPS. In experiments using anti-HMG-1 Abs, mice
were given 0.2 ml preimmune (control) or postimmune (anti-HMG-1)
rabbit antiserum i.p. either 30 min before and 12 h after LPS
administration or 2 and 12 h after LPS administration. Rabbit
anti-HMG-1 antiserum was assayed for specificity and titer to HMG-1
by ELISA and immunoblotting, as previously described (15).
The anti-HMG-1 Abs contained in the antiserum reacted specifically
with HMG-1 and did not cross-react with LPS, other bacterial proteins,
TNF-, or IL-1ß. In these experiments, lungs were harvested 24
h after i.t. administration of PBS with or without endotoxin as
indicated.
HMG-1 exposure
Methoxyfluorane-anesthetized C3H/HeJ mice received 1, 10, or 100 µg HMG-1 i.t. in 50 µl sterile water. Control mice were given 50 µl sterile water i.t. without HMG-1. As a control, 1, 10, or 100 µg of rat albumin (Sigma) in 50 µl distilled water were given i.t., and no increases in lung myeloperoxidase (MPO), wet-dry ratio, or cytokine levels compared with control, unmanipulated mice were found 1, 8, or 24 h after such treatment. Recombinant HMG-1 was prepared as previously described (15), and contained <2.5 ng of LPS per µg of rHMG-1. Similar doses of HMG-1 have been given i.p. in previous studies (15) examining the systemic effects of this molecule. In the present experiments, lungs were harvested 8 or 24 h after the i.t. injections.
MPO assay
MPO activity was assayed as reported previously (16). Excised lungs from three to four mice per treatment group were frozen in liquid nitrogen, weighed, and stored at -86°C. Lungs were homogenized for 30 s in 1.5 ml 20 mM potassium phosphate, pH 7.4, and centrifuged at 4°C for 30 min at 40,000 x g. The pellet was resuspended in 1.5 ml 50 mM potassium phosphate, pH 6.0, containing 0.5% hexadecyltrimethylammonium bromide, sonicated for 90 s, incubated at 60°C for 2 h, and centrifuged. The supernatant was assayed for peroxidase activity corrected to lung weight.
Wet-dry lung weight ratios
All mice used for lung wet-dry weight ratios were of identical ages. Lungs were excised, rinsed briefly in PBS, blotted, and then weighed to obtain the "wet" weight. Lungs were then dried in an oven at 80°C for 7 days to obtain the "dry" weight.
Cytokine ELISA
After the lung vascular bed had been flushed by injecting 5 ml
chilled (4°C) PBS into the right ventricle, the lungs were
homogenized for 30 s in lysis buffer containing 10 mM HEPES, 150
mM NaCl, 1 mM EDTA, 0.6% ipegal, 5 mM PMSF, 1 µg/ml leupeptin, 1
µg/ml aprotinin, 10 µg/ml soybean trypsin inhibitor, and 1 µg/ml
pepstatin. The homogenates were centrifuged at 10,000 rpm at 4°C for
10 min, and the supernatants were collected. Protein content of the
supernatants was determined using the bicinchoninic acid protein assay
kit from Pierce Chemical Co. (Pittsburgh, PA). Immunoreactive IL-1ß,
TNF-, and macrophage-inflammatory protein-2 (MIP-2) were quantitated
using commercially available ELISA kits (R&D Systems, Minneapolis, MN).
With these assays, the threshold of sensitivity for IL-1ß and MIP-2
is 3 pg/ml, and that for TNF- is 10 pg/ml.
Histochemistry
Control or HMG-1 mice were euthanized by cervical dislocation under methoxyfluorane anesthesia 24 h after i.t. injections, and then the chest was opened and the lung vascular bed was flushed by injecting 5 ml cold PBS through the right ventricle of the heart. The lungs were gently infiltrated through the trachea with 1% low melting point agarose (SeaKem, FMC Bioproducts, Rockland, ME) at 42°C. The lungs were removed en bloc and fixed in 4% paraformaldehyde, 0.23 M sucrose solution overnight. Tissue was then embedded, and 5-µm sections were prepared for staining with Gill’s hematoxylin (Fisher, Springfield, NJ).
Statistical analysis
To limit variability and provide appropriate controls, for each experimental condition, groups of animals were prepared and studied at the same time. For each experimental condition, mice in all groups had the same birth date and had been housed together. Separate groups of mice (n = 3 to 9 per group) were used for MPO assays and cytokine analysis. Data are presented as mean ± SEM for each experimental group. One way ANOVA and the Tukey-Kramer multiple comparisons test was used for comparisons between data groups. p < 0.05 was considered significant.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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A). Further increases in lung MPO
were present 24 h after HMG-1 exposure (Fig. 1B). Lung
edema, as measured by wet-dry ratio, was significantly increased 8 and
24 h after HMG-1 administration, compared with controls (Fig. 1).
These effects could not be attributed to the trace amount of endotoxin
coadministered with the HMG-1, because C3H/HeJ mice do not respond to
low doses of endotoxin.
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, and MIP-2 were significantly
elevated in the lungs after administration of doses of HMG-1 as low as
1 µg/mouse (Fig. 2). Histological
examination of tissue sections prepared from the lungs of animals
treated with 100 µg HMG-1 24 h previously revealed evidence of
an acute diffuse inflammatory response, with accumulation of
neutrophils in the interstitial and intraalveolar areas, interstitial
edema, and protein exudation into the alveolar space (Fig. 3). These pathological changes are typically
observed in response to acute lung injury mediated by endotoxin,
TNF-, and other proinflammatory stimuli (6, 17, 22, 23, 24). Because the doses of HMG-1 applied here fall within the
pathologically relevant range seen in sepsis patients or endotoxemic
mice (15), these findings provide direct evidence that
HMG-1 can participate in the mediation of acute lung injury.
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, IL-1ß, and MIP-2. Treatment of mice with
anti-HMG-1 Abs either before or after endotoxin administration
significantly decreased endotoxin-induced neutrophil accumulation into
the lungs (Figs. 4A and B). Further, passive
immunization of mice with anti-HMG-1 Abs before or after endotoxin
exposure significantly attenuated the severity of lung edema produced
by intratracheal instillation of endotoxin (Fig. 4). It was
theoretically possible that the protective effects of anti-HMG-1
were due to decreasing the expression of TNF-, IL-1ß, and MIP-2 in
the lung. However, anti-HMG-1 treatment had no effect on
endotoxin-induced increases in IL-1ß, TNF-, or MIP-2 protein
concentrations (Fig. 5). Thus, the protection
by anti-HMG-1 in endotoxin-induced acute lung injury is specific.
These results demonstrate that HMG-1 is a mediator of acute
inflammatory lung injury.
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(15). The present
experiments show that the delayed release of HMG-1 can participate in
the downstream development of lung injury. This role of HMG-1 in the
pathogenesis of acute lung injury appears to be distinct from any
effects on earlier acting proinflammatory cytokines. In particular,
despite the ameliorative effects of anti-HMG-1 Abs on the
development of lung injury and neutrophil accumulation,
endotoxin-induced increases in pulmonary concentrations of IL-1ß,
TNF-, and MIP-2 were not affected by inhibiting HMG-1. Previous
studies (18) demonstrated that proinflammatory cytokines,
including IL-1ß and TNF-, induce production of HMG-1. The present
findings are consistent with HMG-1 being a distal inflammatory
mediator, with delayed release after cellular exposure to endotoxin or,
more likely, with release induced primarily by proinflammatory
cytokines, such as IL-1ß and TNF-, the expression of which is
rapidly increased by endotoxin.
Although anti-HMG-1 treatment significantly decreased lung edema
and neutrophil accumulation, such therapy did not completely ameliorate
the development of lung injury as compared with controls. These results
indicate that whereas HMG-1 participates in endotoxin-induced lung
injury, other mediators also are involved. It is likely that IL-1ß,
TNF-, and MIP-2 participate in the early development of acute lung
injury (3, 6, 16, 19, 20, 21); the levels of these mediators
were increased in the lungs of endotoxin-treated mice even when
anti-HMG-1 was administered. Blockade of each of these cytokines
ameliorates endotoxin-induced lung damage (17, 22).
Instillation of IL-1ß, TNF-, or MIP-2 into the lungs leads to
neutrophil accumulation, interstitial edema, and histological changes
consistent with inflammatory injury (23, 24). These
proinflammatory cytokines are present in bronchoalveolar lavage
specimens from animals or patients with acute lung injury (17, 19, 20, 21, 22, 23, 24, 25). The delayed kinetics of HMG-1 release, associated with
its contributory role in acute lung injury, point to HMG-1 as a
potential target for therapeutic intervention. However, because
inhibition of HMG-1 does not completely prevent inflammatory injury to
the lungs, it is likely that effective strategies for acute lung injury
should focus on inhibiting the pathological effects of both early
(e.g., TNF- and IL-1ß) and late (e.g., HMG-1) mediators.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Edward Abraham, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Box C272, 4200 East Ninth Avenue, Denver, CO 80262.
3 Abbreviations used in this paper: HMG-1, high mobility group protein-1; MIP-2, macrophage inflammatory protein-2; i.t., intratracheally; MPO, myeloperoxidase.
Received for publication May 31, 2000. Accepted for publication July 21, 2000.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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 C. K. Zetterstrom, M.-L. Strand, and O. Soder The high mobility group box chromosomal protein 1 is expressed in the human and rat testis where it may function as an antibacterial factor Hum. Reprod., November 1, 2006; 21(11): 2801 - 2809. [Abstract] [Full Text] [PDF]
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X.-Q. Wang, K. Bdeir, S. Yarovoi, D. B. Cines, W. Fang, and E. Abraham Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury J. Immunol., October 15, 2006; 177(8): 5550 - 5557. [Abstract] [Full Text] [PDF]
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W. Jiang and D. S. Pisetsky The Role of IFN-{alpha} and Nitric Oxide in the Release of HMGB1 by RAW 264.7 Cells Stimulated with Polyinosinic-Polycytidylic Acid or Lipopolysaccharide. J. Immunol., September 1, 2006; 177(5): 3337 - 3343. [Abstract] [Full Text] [PDF]
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E. N. Ogawa, A. Ishizaka, S. Tasaka, H. Koh, H. Ueno, F. Amaya, M. Ebina, S. Yamada, Y. Funakoshi, J. Soejima, et al. Contribution of High-Mobility Group Box-1 to the Development of Ventilator-induced Lung Injury Am. J. Respir. Crit. Care Med., August 15, 2006; 174(4): 400 - 407. [Abstract] [Full Text] [PDF]
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 J.-B. Kim, J. Sig Choi, Y.-M. Yu, K. Nam, C.-S. Piao, S.-W. Kim, M.-H. Lee, P.-L. Han, J.-s. Park, and J.-K. Lee HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J. Neurosci., June 14, 2006; 26(24): 6413 - 6421. [Abstract] [Full Text] [PDF]
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S. Liu, D. B. Stolz, P. L. Sappington, C. A. Macias, M. E. Killeen, J. J. Tenhunen, R. L. Delude, and M. P. Fink HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers Am J Physiol Cell Physiol, April 1, 2006; 290(4): C990 - C999. [Abstract] [Full Text] [PDF]
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J. S. Park, F. Gamboni-Robertson, Q. He, D. Svetkauskaite, J.-Y. Kim, D. Strassheim, J.-W. Sohn, S. Yamada, I. Maruyama, A. Banerjee, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors Am J Physiol Cell Physiol, March 1, 2006; 290(3): C917 - C924. [Abstract] [Full Text] [PDF]
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 H. Wang, W. Li, J. Li, B. Rendon-Mitchell, M. Ochani, M. Ashok, L. Yang, H. Yang, K. J. Tracey, P. Wang, et al. The Aqueous Extract of a Popular Herbal Nutrient Supplement, Angelica sinensis, Protects Mice against Lethal Endotoxemia and Sepsis J. Nutr., February 1, 2006; 136(2): 360 - 365. [Abstract] [Full Text] [PDF]
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S. Mitola, M. Belleri, C. Urbinati, D. Coltrini, B. Sparatore, M. Pedrazzi, E. Melloni, and M. Presta Cutting Edge: Extracellular High Mobility Group Box-1 Protein Is a Proangiogenic Cytokine J. Immunol., January 1, 2006; 176(1): 12 - 15. [Abstract] [Full Text] [PDF]
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G. Srikrishna, O. Turovskaya, R. Shaikh, R. Newlin, D. Foell, S. Murch, M. Kronenberg, and H. H. Freeze Carboxylated Glycans Mediate Colitis through Activation of NF-{kappa}B J. Immunol., October 15, 2005; 175(8): 5412 - 5422. [Abstract] [Full Text] [PDF]
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W. Jiang, J. Li, M. Gallowitsch-Puerta, K. J. Tracey, and D. S. Pisetsky The effects of CpG DNA on HMGB1 release by murine macrophage cell lines J. Leukoc. Biol., October 1, 2005; 78(4): 930 - 936. [Abstract] [Full Text] [PDF]
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X. Lin, H. Yang, T. Sakuragi, M. Hu, L. L. Mantell, S. Hayashi, Y. Al-Abed, K. J. Tracey, L. Ulloa, and E. J. Miller {alpha}-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L583 - L590. [Abstract] [Full Text] [PDF]
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H. Yang, H. Wang, C. J. Czura, and K. J. Tracey The cytokine activity of HMGB1 J. Leukoc. Biol., July 1, 2005; 78(1): 1 - 8. [Abstract] [Full Text] [PDF]
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J. Y. Kim, J. S. Park, D. Strassheim, I. Douglas, F. Diaz del Valle, K. Asehnoune, S. Mitra, S. H. Kwak, S. Yamada, I. Maruyama, et al. HMGB1 contributes to the development of acute lung injury after hemorrhage Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L958 - L965. [Abstract] [Full Text] [PDF]
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C. Schlueter, H. Weber, B. Meyer, P. Rogalla, K. Roser, S. Hauke, and J. Bullerdiek Angiogenetic Signaling through Hypoxia: HMGB1: An Angiogenetic Switch Molecule Am. J. Pathol., April 1, 2005; 166(4): 1259 - 1263. [Abstract] [Full Text] [PDF]
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T. J. Murphy, H. M. Paterson, S. Kriynovich, Y. Zang, E. A. Kurt-Jones, J. A. Mannick, and J. A. Lederer Linking the "two-hit" response following injury to enhanced TLR4 reactivity J. Leukoc. Biol., January 1, 2005; 77(1): 16 - 23. [Abstract] [Full Text] [PDF]
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H. Ueno, T. Matsuda, S. Hashimoto, F. Amaya, Y. Kitamura, M. Tanaka, A. Kobayashi, I. Maruyama, S. Yamada, N. Hasegawa, et al. Contributions of High Mobility Group Box Protein in Experimental and Clinical Acute Lung Injury Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1310 - 1316. [Abstract] [Full Text] [PDF]
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T. Goto, A. Ishizaka, F. Kobayashi, M. Kohno, M. Sawafuji, S. Tasaka, E. Ikeda, Y. Okada, I. Maruyama, and K. Kobayashi Importance of Tumor Necrosis Factor-{alpha} Cleavage Process in Post-Transplantation Lung Injury in Rats Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1239 - 1246. [Abstract] [Full Text] [PDF]
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G. Chen, J. Li, M. Ochani, B. Rendon-Mitchell, X. Qiang, S. Susarla, L. Ulloa, H. Yang, S. Fan, S. M. Goyert, et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms J. Leukoc. Biol., November 1, 2004; 76(5): 994 - 1001. [Abstract] [Full Text] [PDF]
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 A. Rouhiainen, J. Kuja-Panula, E. Wilkman, J. Pakkanen, J. Stenfors, R. K. Tuominen, M. Lepantalo, O. Carpen, J. Parkkinen, and H. Rauvala Regulation of monocyte migration by amphoterin (HMGB1) Blood, August 15, 2004; 104(4): 1174 - 1182. [Abstract] [Full Text] [PDF]
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D. Messmer, H. Yang, G. Telusma, F. Knoll, J. Li, B. Messmer, K. J. Tracey, and N. Chiorazzi High Mobility Group Box Protein 1: An Endogenous Signal for Dendritic Cell Maturation and Th1 Polarization J. Immunol., July 1, 2004; 173(1): 307 - 313. [Abstract] [Full Text] [PDF]
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 Z. Zhou, Y. Yamamoto, F. Sugai, K. Yoshida, Y. Kishima, H. Sumi, H. Nakamura, and S. Sakoda Hepatoma-derived Growth Factor Is a Neurotrophic Factor Harbored in the Nucleus J. Biol. Chem., June 25, 2004; 279(26): 27320 - 27326. [Abstract] [Full Text] [PDF]
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J. P. Mizgerd, M. M. Lupa, J. Hjoberg, J. C. Vallone, H. B. Warren, J. P. Butler, and E. S. Silverman Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with combined deficiencies of all signaling receptors for TNF and IL-1 Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1302 - L1310. [Abstract] [Full Text] [PDF]
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J. S. Park, D. Svetkauskaite, Q. He, J.-Y. Kim, D. Strassheim, A. Ishizaka, and E. Abraham Involvement of Toll-like Receptors 2 and 4 in Cellular Activation by High Mobility Group Box 1 Protein J. Biol. Chem., February 27, 2004; 279(9): 7370 - 7377. [Abstract] [Full Text] [PDF]
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 R. Palumbo, M. Sampaolesi, F. De Marchis, R. Tonlorenzi, S. Colombetti, A. Mondino, G. Cossu, and M. E. Bianchi Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation J. Cell Biol., February 2, 2004; 164(3): 441 - 449. [Abstract] [Full Text] [PDF]
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 H. Yang, M. Ochani, J. Li, X. Qiang, M. Tanovic, H. E. Harris, S. M. Susarla, L. Ulloa, H. Wang, R. DiRaimo, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1 PNAS, January 6, 2004; 101(1): 296 - 301. [Abstract] [Full Text] [PDF]
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N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]
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J. S. Park, J. Arcaroli, H.-K. Yum, H. Yang, H. Wang, K.-Y. Yang, K.-H. Choe, D. Strassheim, T. M. Pitts, K. J. Tracey, et al. Activation of gene expression in human neutrophils by high mobility group box 1 protein Am J Physiol Cell Physiol, April 1, 2003; 284(4): C870 - C879. [Abstract] [Full Text] [PDF]
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B. Rendon-Mitchell, M. Ochani, J. Li, J. Han, H. Wang, H. Yang, S. Susarla, C. Czura, R. A. Mitchell, G. Chen, et al. IFN-{gamma} Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism J. Immunol., April 1, 2003; 170(7): 3890 - 3897. [Abstract] [Full Text] [PDF]
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C. Fiuza, M. Bustin, S. Talwar, M. Tropea, E. Gerstenberger, J. H. Shelhamer, and A. F. Suffredini Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells Blood, April 1, 2003; 101(7): 2652 - 2660. [Abstract] [Full Text] [PDF]
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Huan Yang, Haichao Wang, C. J. Czura, and K. J. Tracey HMGB1 as a cytokine and therapeutic target Innate Immunity, December 1, 2002; 8(6): 469 - 472. [Abstract] [PDF]
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U. Andersson, H. Erlandsson-Harris, H. Yang, and K. J. Tracey HMGB1 as a DNA-binding cytokine J. Leukoc. Biol., December 1, 2002; 72(6): 1084 - 1091. [Abstract] [Full Text] [PDF]
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L. Ulloa, M. Ochani, H. Yang, M. Tanovic, D. Halperin, R. Yang, C. J. Czura, M. P. Fink, and K. J. Tracey Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation PNAS, September 17, 2002; 99(19): 12351 - 12356. [Abstract] [Full Text] [PDF]
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H. WANG, H. YANG, C. J. CZURA, A. E. SAMA, and K. J. TRACEY HMGB1 as a Late Mediator of Lethal Systemic Inflammation Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1768 - 1773. [Full Text] [PDF]
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J. Fan, R. D. Ye, and A. B. Malik Transcriptional mechanisms of acute lung injury Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1037 - L1050. [Abstract] [Full Text] [PDF]
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C. J. Czura, Haichao Wang, and K. J. Tracey Dual roles for HMGB1: DNA binding and cytokine Innate Immunity, August 1, 2001; 7(4): 315 - 321. [Abstract] [PDF]
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B. Degryse, T. Bonaldi, P. Scaffidi, S. Muller, M. Resnati, F. Sanvito, G. Arrigoni, and M. E. Bianchi The High Mobility Group (Hmg) Boxes of the Nuclear Protein Hmg1 Induce Chemotaxis and Cytoskeleton Reorganization in Rat Smooth Muscle Cells J. Cell Biol., March 19, 2001; 152(6): 1197 - 1206. [Abstract] [Full Text] [PDF]
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