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Byline: Pelagia G. Tsoutsou (1,4), Konstantinos I. Gourgoulianis (1), Efthymia Petinaki (2), Maria Mpaka (1), Smaragda Efremidou (2), Antonios Maniatis (2), Pashalis Adam Molyvdas (3) Keywords: idiopathic pulmonary fibrosis; cell adhesion molecules; interstitial lung disease Abstract: In order to test the serum levels of ICAM-1, ICAM-2 and ICAM-3 in patients with idiopathic pulmonary fibrosis (IPF), twenty patients with IPF and eleven with secondary interstitial fibrosis (SIF), as well as forty healthy volunteers (HV) were studied. Serum intracellular adhesion molecules (ICAM) 1, 2 and 3 were assessed by ELISA. Functional respiratory tests, which included spirometry and lung diffusing capacity were simultaneously performed. Median values of serum ICAM-1 and ICAM-2 were higher in the patients' than in the healthy volunteers' (HV) group: IPF group: 946.60 ng/ml and 400.14 ng/ml SIF group: 901.58 ng/ml and 378.27 ng/ml HV group: 308.40 ng/ml and 217.55 ng/ml, respectively (p &lt 0.05). ICAM-3 serum levels were equal between the three groups. ICAM-2 negatively correlated to DLCO values. (p &lt 0.005). It can be concluded that ICAM 1 and 2 are elevated in the sera of patients with pulmonary fibrosis. ICAM-2 might be associated with a more impaired clinical status. Author Affiliation: (1) Pulmonary Department, University of Thessaly, Greece (2) Department of Microbiology, University of Thessaly, Greece (3) Physiology Department, University of Thessaly, Greece (4) Nikis 33, Syntagma Athens, 105 57, Greece Article History: Registration Date: 01/01/2004

Byline: Satoshi Gando (1), Takashi Kameue (1), Naoyuki Matsuda (1), Atsushi Sawamura (1), Mineji Hayakawa (1), Hirokatsu Kato (1) Keywords: acute lung injury (ALI); acute respiratory distress syndrome (ARDS); coagulation; inflammation; neutrophil; soluble adhesion molecules Abstract: To determine the existence of a close link between inflammation and coagulation in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and to examine their prognostic value in the development of ARDS and clinical outcome, we made a prospective cohort study. The study subjects consisted of 57 patients: 19 patients with ARDS and 38 patients with ALI as defined by a Lung Injury Score of aY=2.5 and 1.0 to less than 2.5, respectively. According to the outcome, the patients were subdivided into the survivors and the nonsurvivors. Ten normal healthy volunteers served as control subjects. Plasma levels of soluble L-, P-, and E-selectins, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (sTM), and neutrophil elastase were measured within 24 h after the diagnosis of ALI or ARDS. The number of systemic inflammatory response syndrome (SIRS) criteria being met by the patients and the disseminated intravascular coagulation (DIC) scores were determined simultaneously. The number of SIRS criteria and the DIC scores of the patients with ALI or ARDS showed high values, and more than half of the patients were complicated by DIC. The levels of sL-selectin in both groups of the patients were significantly lower than those of the control subjects. All other soluble adhesion molecules, neutrophil elastase, and sTM in the patients with ALI and ARDS were markedly elevated than those in the control subjects. The levels sICAM-1, sVCAM-1, and sTM in the ARDS patients significantly increased compared with the ALI patients. The number of SIRS criteria and the DIC scores in the nonsurvivors showed higher values than those in the survivors. In addition, we found significant differences in the levels of soluble adhesion molecules, neutrophil elastase, and sTM between the survivors and the nonsurvivors. {In conclusion, we found a concurrent activation of both inflammation and coagulation in the patients with ALI or ARDS. The results also suggest that systemic activation of inflammation and coagulation associated with endothelial injury has prognostic value for the development of ARDS and poor outcome.} Author Affiliation: (1) Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido, University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, Japan Article History: Registration Date: 20/12/2004

Byline: Lauree R. Thompson (1), Susan E. Keeney (1), Donna Tarrant (1), Elizabeth Rudloff (1), Dara V. Dallas (1), Frank C. Schmalstieg (1) Keywords: inflammation; endotoxin; E-selectin; P-selectin; soluble L-selectin Abstract: Sublethal doses of LPS result in increased tolerance to high concentrations of oxygen and this is associated with decreased pulmonary inflammation in a rat model. To investigate the mechanism of decreased neutrophil influx into the lung in this model, we measured levels of mRNA in the lung for the endothelial adhesion molecules, E-selectin and P-selectin. Immunostaining for E-selectin protein was also done in rat lungs, as well as measurement of soluble L-selectin in the blood. These levels were measured in the lungs of adult rats injected with 0.5 mg/kg LPS or placebo at 0 and 24 h and exposed to &gt 95% O.sub.2 for 60 h. Oxygen exposure resulted in significant increases in both E- and P-selectin mRNA and in E-selectin protein after 60 h. LPS resulted in an early rise in E-selectin protein followed by a decline to less than control (saline/O.sub.2) levels at 60 h. Messenger RNA for E-selectin followed a similar trend, although there were no differences at 60 h between LPS and control groups exposed to O.sub.2. P-selectin mRNA expression did not significantly differ between LPS and control O.sub.2 groups. Soluble L-selectin levels decreased by 6 h after LPS infusion and were significantly lower than saline/O.sub.2 controls through 24 h, suggesting binding to endothelium. In conclusion, the decrease in E-selectin expression on the surface of pulmonary endothelium after LPS could contribute to decreased inflammation in this model of oxygen toxicity. Soluble L-selectin may serve a further anti-inflammatory role after LPS infusion by binding to pulmonary endothelium. Author Affiliation: (1) Departments of Pediatrics and Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, Texas Article History: Registration Date: 08/10/2004

Byline: Karl-Gustav Kolbeck (1,2), Eliane Sardh (3), Hans Gyllenhammar (3,4), Lena Palmberg (5), Kjell Larsson K (5), Jan Palmblad (3) Keywords: Airway inflammation; swine dust; nitric oxide; adhesion molecules Abstract: Short-time exposure to swine dust causes an intense airways inflammation and symptoms of systemic inflammation in healthy volunteers. Here, we sought to study whether this response involved signs of endothelial cell activation. Peripheral blood cell counts and plasma levels of sE-selectin, sP-selectin, sICAM-1, interleukin-8, nitrite and nitrate were measured in blood samples from 17 healthy subjects before and after a 3-hr exposure to swine dust in a swine confinement building. Dust exposure induced a 3-fold increase of blood neutrophil p = 0.0009) and 1.5-fold increase of monocyte counts (p = 0.0047). IL-8 was detected in 15 individuals after exposure (p = 0.001). Endothelial cell markers such as sICAM and nitrate increased by 10 and 34% resp. (p = 0.011 and 0.017), whereas sE-selectin remained unchanged and sP-selectin was reduced by 15% (p = 0.031). Thus, short time exposure to swine dust induced a systemic inflammatory response with evidence of endothelial and inflammatory cell activation. Author Affiliation: (1) Division of Respiratory Medicine and Allergology at Department of Medicine, Huddinge University Hospital, Huddinge, Sweden (2) The Department of Respiratory Medicine and Allergology, Huddinge University Hospital, S-141 86, Stockholm, Sweden (3) Center for Inflammation and Hematology Research, Clinical Research Center, Novum, Sweden (4) Division of Hematology at Department of Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden (5) National Institute for Working Life, Solna, Sweden Article History: Registration Date: 12/10/2004

Byline: Yuji Saito (1), Chizuko Nakagawa (1), Hiromi Uchida (1), Fumihiko Sasaki (1), Hiroki Sakakibara (1) Keywords: adhesion molecules; cAMP; flow cytometry Abstract: In this study we investigated the effect of adrenomedullin (AM) on fMLP-mediated activation of human neutrophils. AM partially, but significantly, suppressed fMLP-induced upregulation of CD11b expression. The inhibitory effects of AM upon fMLP-induced upregulation of CD11b expression were completely blocked by CGRP [8--37], a CGRP receptor antagonist. AM significantly increased cAMP content in neutrophils and SQ-22,536, an adenylate cyclase inhibitor, and KT-5720, a PKA inhibitor, significantly blocked the inhibitory effects of AM upon fMLP-induced upregulation of CD11b expression. This study indicates that binding of AM to the CGRP receptor suppresses fMLP-induced upregulation of CD11b expression of human neutrophils by increasing intracellular cAMP levels. AM may play an important role in the regulation of inflammatory processes, especially in the binding of neutrophils to vascular endothelial cells and subsequent neutrophil emigration evident in acute pulmonary inflammation. Author Affiliation: (1) Division of Respiratory Medicine and Allergy, Fujita Health University School of Medicine, 1--98, Dengakugakubo, Kutsukake, Toyoake-city, Aichi, 470--1192, Japan Article History: Registration Date: 17/10/2004

Byline: Helena Yusuf-Makagiansar (1), Irwan T. Makagiansar (1), Teruna J. Siahaan (1) Keywords: leukocyte infiltration; T-lymphocytes; adhesion molecules; apoptosis; LFA-1-peptide Abstract: Tissue inflammation is characterized by aggravated leukocyte infiltration into the sites of inflammation. The mechanism requires the interactions of leukocyte adhesion-molecules and their ligands in the inflamed tissues. In this study, we demonstrate that a cyclic peptide cLAB.L [cyclo1, 12-PenITDGEATDSGC], derived from the 'inserted' or I-domain of LFA-1 is able to inhibit the adherence of T-lymphocytes to the epithelial cell monolayers. This inhibition has been thought to involve the disruption of LFA-1/ICAM-1 interaction. The heterotypic adhesion of phorbol ester-activated Molt-3 cells and IFN-I3-induced Caco-2 monolayers was inhibited upon treatment of the monolayers with monoclonal antibodies (MAbs) to adhesion molecules or with cLAB.L peptide. The adhesion can be inhibited by MAbs to ICAM-1, ICAM-2, and VCAM-1, and cLAB.L peptide in a concentration-dependent manner. However, none of the individual uses of these molecules led to a total inhibition. The inhibitory activity of cLAB.L is greatly reduced by low temperature and the absence of cell activation. Treatment of cLAB.L peptide may trigger an early event of apoptosis on activated but not on non-activated Molt-3 cells no indication of peptide-induced apoptosis was found on Caco-2 cells. Taken together, data from this work suggest that cLAB.L may have applications to direct cell-targeted delivery during tissue inflammation. Author Affiliation: (1) Department of Pharmaceutical Chemistry, Simons Research Laboratories, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas, 66047 Article History: Registration Date: 17/10/2004

Byline: Giuseppe Montalto (1), Lydia Giannitrapani (1), Maurizio Soresi (1), Lucrezia Virruso (2), Daniela di Martino (1), Roberto Gambino (2), Antonio Carroccio (1), Melchiorre Cervello (2) Keywords: chronic liver disease; E-selectin; adhesion molecule; treatment; [alpha]-interferon Abstract: E-selectin, an adhesion molecule of the selectin family, is involved in leukocyte adhesion to the endothelium and in the cellular immunological reactions. Expression of this molecule, in fact, is physiologically absent, but it becomes evident on sinusoidal lining cells during inflammatory liver disease. The aim of this study was to evaluate the behavior of E-selectin in chronic hepatitis C (CH-C) patients with persistently normal transaminase in comparison to patients with CH-C and elevated transaminase, and its changes during alpha-interferon therapy. Immunohistochemical localization of E-selectin was also performed on liver tissue specimens of both groups. Fifty-eight subjects were divided into 3 groups: group A included 18 patients with CH-C and persistently normal transaminase group B 20 patients with CH-C and persistently elevated transaminase levels and group C included 20 healthy subjects, representing the control group. The first two groups were treated with r-IFN [alpha] at a dose of 6 MU 3 times a week for 3 months and followed-up with 3 MU 3 times a week for another 3 months. Serum baseline values of E-selectin in groups A and B were significantly higher than those in group C (P &lt 0.04), but there was no difference between groups A and B. Furthermore, there was a trend toward higher E-selectin values as histological severity increased (r = 0.69 P &lt 0.0001). Post-treatment E-selectin serum values showed a moderate decrease in both groups, but only among responder patients while E-selectin levels were unchanged in non responders. Immunohistochemical localization showed no staining for E-selectin in normal liver specimens, while there was a quite similar staining for E-selectin in the two groups of patients. In conclusion, this study shows that serum E-selectin levels in patients with CH-C and persistently normal transaminase are higher than in controls and they are associated with severity of liver disease. Liver of these patients express E-selectin molecules, suggesting an activation of the immune system almost identical to that of patients with CH-C and elevated transaminase. In both groups only responder patients showed a moderate decrease below baseline serum values. Author Affiliation: (1) Istituto di Medicina Interna e Geriatria, Universita di Palermo, via del Vespro 141, 90127 Cattedra di Medicina Interna, Palermo, Italy (2) Istituto di Biologia dello Sviluppo, Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy Article History: Registration Date: 17/10/2004

Byline: Masako Ohnishi (1), Noriaki Imanishi (1) Abstract: The role of P-selectin in the accumulation of neutrophils at acute dermal inflammatory sites induced by chemoattractants, LTB4 and IL-8 was investigated in the mouse. A mouse P-selectin-human IgG chimera bound to mouse neutrophils in vitro in a calcium-dependent manner, as detected by flow cytometry. A rat monoclonal antibody (mAb) against mouse P-selectin, RB40.34 abolished P-selectin-IgG chimera binding to mouse neutrophils, but a control antibody did not. Intradermal injection of LTB4 at a dose of 100 ng/site caused neutrophil accumulation to increase by 3-4 fold, as detected by measuring myeloperoxidase activity. Neutrophil extravasation to perivascular tissue was detected by histochemical observation. The intravenous injection of RB40.34 or the specific LTB4 antagonist, SM-15178, at doses at 5 mg/kg attenuated the accumulation of neutrophils by 55.6% and 70.3%, respectively, but a control antibody showed no effect. Similarly, intradermal administration of IL-8 at a dose of 5 ug/site induced significant neutrophil migration into the interstitial tissue of the skin, as followed by measuring myeloperoxidase activity and histopathologic analysis. The intravenous injection of RB40.34 at a dose of 5 mg/kg reduced the neutrophil accumulation by 59.2% in contrast, a control antibody showed no effect. To our knowledge, this is the first direct demonstration that P-selectin plays a substantial role in LTB4and IL-8-induced neutrophil accumulation in mouse skin. Author Affiliation: (1) Research Center, Sumitomo Pharmaceuticals, 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka, 554--0022, Japan Article History: Registration Date: 05/10/2004

Byline: Andrea K. Hubbard (1), Charles Giardina (2) Abstract: In a mouse model of silica (SI) induced lung injury, SI exposure increases expression of intercellular adhesion molecule-1 (ICAM-1) on lung (alveolar/interstitial) macrophages and alveolar type II epithelial cells. To investigate the regulation of SI induced ICAM-1 expression on mouse macrophages, freshly isolated macrophages (alveolar, peritoneal) and macrophage cell lines (MH-S, RAW 264.7) were evaluated for ICAM-1 expression elicited by the particle silica ([alpha] quartz 20 ug/ml 6 ug/cm.sup.2) or the inflammatory cytokine, TNF[alpha] (20 ng/ml). TNF[alpha] significantly increased ICAM-1 expression in all cell types whereas SI elicited an increase in peritoneal macrophages (PM) and the cell line, MH-S. This pattern of increased expression was confirmed by immunocytochemistry. To investigate the regulation of ICAM-1 expression, PM were incubated with SI, TNF[alpha] or media concomitantly with anti-TNF[alpha] antibody, the antioxidant, NAC, or the iNOS synthase inhibitor, L-NAME. Both anti-TNF[alpha] and NAC, but not L-NAME, inhibited elicited (TNF[alpha], SI) as well as constitutive (media) ICAM-1 expression. These data demonstrate that both inflammatory cytokines and inorganic particles can increase ICAM-1 expression on mouse macrophages and that this expression is mediated, in part, by TNF[alpha] and reactive oxygen species. Author Affiliation: (1) Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, 06269 (2) Department of Molecular and Cellular Biology, University of Connecticut, Storrs, Connecticut, 06269 Article History: Registration Date: 09/10/2004

Byline: Kin'ya Abe (1), Toru Arai (1), Masahide Mori (1), Hiroshi Kida (1), Sho Goya (1), Hiroto Matsuoka (1), Tadashi Osaki (1), Isao Tachibana (1), Seiji Hayashi (1) Abstract: The selectin family adhesion molecules exert a crucial role in accumulation of leukocytes at the site of inflammation. To test the biological effects of soluble selectin on lung inflammation, we introduced an expression plasmid vector of soluble selectin gene via HVJ-liposome into a murine model of LPS-induced lung injury. The myeloperoxidase activity in LPS-injected mice was suppressed by the in vivo injection of soluble P-selectin gene relative to control mice. On the contrary, soluble E- or L-selectin genes did not exert suppressive effects. Our observations suggest that P-selectin plays a crucial role in the initial steps of lung inflammation, and exogenous introduction of soluble P-selectin by in vivo gene transfer method may be a useful strategy for regulating inflammation of the lung. Author Affiliation: (1) Department of Molecular Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita-city, Osaka, 565--0871, Japan Article History: Registration Date: 30/09/2004

Byline: Michael S. Mulligan (1), Alex B. Lentsch (1), Thomas P. Shanley (1), Masayuki Miyasaka (2), Kent J. Johnson (1), Peter A. Ward (1) Abstract: Acute hemorrhagic lung injury occurs in humans with anti-GBM antibody (Goodpasture's syndrome), however, the mechanism of this injury is still largely unknown. To date, treatment has been confined to steroids and plasmaphoresis. Infusion of anti-GBM antibody into rats caused lung injury with intra-alveolar hemorrhage and intrapulmonary accumulation of neutrophils. Lung injury was dependent on the presence of neutrophils and complement and required both TNF[alpha] and IL-1. Experiments employing blocking antibodies to adhesion molecules demonstrated requirements for the [beta].sub.1 integrin VLA-4, [beta].sub.2 integrins LFA-1 and Mac-1, and L-selectin. The endothelial cell adhesion molecules, E-selectin and ICAM-1, were also required for the full development of lung injury. Inhibition of TNF[alpha] or IL-1 or adhesion molecules reduced both lung injury and tissue neutrophil accumulation. Thus, this study underscores cytokine and adhesion molecule requirements for neutrophil mediated injury in lung and kidney caused by anti-GBM, suggesting potential targets for the treatment of Goodpasture's syndrome in humans. Author Affiliation: (1) Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 (2) Department of Bioregulation, Osaka University Medical School, Japan Article History: Registration Date: 03/10/2004

Byline: Steven H. Zuckerman (1), Jason Gustin (2), Glenn F. Evans (1) Abstract: Microglial cell activation plays a central role in acute and chronic inflammatory processes associated with neurodegeneration. As macrophage activation is generally associated with the up-regulation of specific surface antigens, the expression of CD54, and CD29 were evaluated on CD11b positive neonatal rat microglial cell cultures by flow cytometry. These cells when exposed to lipopolysaccharide, LPS, and gamma interferon, IFNI3, exhibited a 2--3 fold increase in CD54 expression, an increase in CD29 and no change in CD11b. Maximal increases in CD54 and CD29 staining on CD11b positive microglial cells were apparent 20--24 h after LPS and IFNI3 while nitrite production reflecting inducible nitric oxide synthase activity, continued to increase. The increases in CD29 and CD54 staining were inhibited in a dose dependent manner by agents which increased intracellular cAMP levels including 100 uM 8-bromoadenosine 3 :5 -cyclic monophosphate but not 8-bromoadenosine monophosphate, the phosphodiesterase inhibitor isobutyl methylxanthine and by direct activation of adenylate cyclase with forskolin. Concomitant with the dose dependent decreases in CD29 and CD54 staining were increases in intracellular cAMP and reduced TNF secretion. These results suggest that regulation of CD29 and CD54 expression on activated microglial cells involves a cAMP dependent pathway. Author Affiliation: (1) Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, Indiana, 46285 (2) Department of Biology, DePauw University, Greencastle, Indiana Article History: Registration Date: 03/10/2004