The molecules involved in the cell adhesion have been extensively studied in recent years, and our understanding of adhesion has advanced in molecular basis. Although it seems to be clear that the adhesion between leukocytes and endothelial cells or extracellular matrix proteins has a key role in the inflammatory reaction, much attention has little been paid so far, particularly in the clinical field.
In this review, recent progress and details of the functional and structural aspects of the adhesion molecules were summarized. Understanding of the molecular mechanism of inflammation by focusing on the cell-cell and cell-matrix interaction may contribute to clarify the pathogenesis of the disease, and to develop a new strategy against the disease.

View full abstract

We isolated cDNA of the whole genome of hepatitis C virus (HCV) from a single Japanese patient. HCV genome was about 9.4 kb in length, and encoded a single polyprotein consisting of 3010 to 3014 aa. The hydropathic profile of HCV polyprotein was similar to those of flaviviruses and pestiviruses, and the ccnsensus sequences of serine protease, helicase and RNA-dependent RNA polymerase of these viruses were also found in HCV polyprotein. Thus HCV is a member of new virus family related to flaviviruses and pestiviruses.
Our isolated cDNA clone, HCV-N, had 78% of nucleotide sequence homology and 84% of amino acid sequence homology with an American isolate, HCV-1, but 91-92% and 93-94% with other Japanese isolates, respectively. Thus Japanese isolates belong to a different type of HCV from an American isolate. However, the nucleotide sequence of 5'-non-coding region was so conserved among these isolates by 99-100% of homology that this region was useful to detect HCV RNA sequence beyond viral heterogeneity.
Using our isolated cDNA clones of HCV, we expressed several viral peptides in Escherichia coli and used to detect anti-HCV antibodies in patients' sera. Anticore peptide antibody was the most efficiently detected in hepatitis C patients. The combined use of anti-core and anti-NS 3/NS 4/NS 5 antibody assays was more efficient for the diagnosis of hepatitis C and the screening of blood donors.

View full abstract

Ca-antagonists, which are clinically used as antihypertensive and protectant against troubles in coronary and cerebral arteries, are now reported to possess various other actions to ameliorate the inflammatory diseases. We found that dihydropyridinetype Ca-antagonists suppressed carrageenan paw edema of rats and ischemic paw edema of mice. The most effective was nilvadipine which inhibited also O^-₂ production of rat peritoneal leukocytes stimulated by Ca-ionophore, f-MLP and PMA. This drug is possible to slow down the development of atherosclerosis for which antioxidant character of drug is recently evaluated. Oxidized LDL must be low by antioxidant treatment Nifedipine is reported to enhance the analgestic action of morphine and the survival of rats which received transplantation of liver kept in nisoldipine increased without immunosuppressants.

View full abstract

Natural bactericidal resistance of Mycobacterium bovis BCG is under the control of a single gene, Bcg. The development of lung granulomas in susceptible (Bcg^s) and resistant (Bcg^r) mice was studied in two sets of Bcg-congenic systems, the BALB/c (Bcg^s) -C.D2 (BALB/c.Bcg^r) pair and the B10. A (Bcg^s) -B10. A^r (Bcg^r) pair, by using BCG as well as foregin-body granuloma-inducing agents, dextran beads. Large lung granulomas induced by the intratracheal challenge of either BCG or dextran beads developed in Bcg^s mice. By contrast, minimal lesions were produced in Bcg^r mice given BCG or dextran beads. Aqueous extracts prepared from pulmonary granuloma lesions induced in Bcg^s mice by either BCG or dextran beads contained a large amount of interleukin 1 (IL-1) activity but not IL-2 or IL-4 activity. Very low IL-1 activity was detectable in extracts from Bcg^r mice challenged with BCG and dextran beads. The activity of IL-1 was correlated with activity/size of the granulomatous inflammation in mice.
These results incucate that the Bcg gene has pleiotropic effects on the development of granulomas induced by either BCG or nonspecific foreign body agents (dextran beads) and that macrophage-derived cytokines participate in granuloma formation.

View full abstract

We examined the mechanism of the synergistic action of elastase and hydrogen peroxide on vascular endothelial cell injury, using cultured endothelial cells prelabeled with ⁵¹Cr. Co-existence with elastase (10 μg/ml) and hydrogen peroxide (50 μM) induced severe endothelial cell injury, although each one of them alone had no such cytotoxicity at all. This synergistic effect was not based on the suppressed activities of the protective enzymes against oxidative stress, such as catalase and glutathione peroxidase, but related to hydroxylradicals, because this injury was inhibited by deferoxamine mesylate. Moreover, α-1 antitrypsin and α-2 macroglobulin, which are physiologically present in the serum as protease inhibitors, showed protective action on the synergistic effect.
Therefore, some protease inhibitors may be benificial to the diseases related to activated leukocytes, because they will suppress the endothelial cell injury elicited by active oxygen species released from leukocytes by inhibiting protease activity of leukocytes.

View full abstract

The effects of intravenous administration with dihomo-γ-linolenic acid (DGLA) on fatty acid com-position in the total phospholipid fraction of plasma and spleen cells, and delayed-type hypersensitivity (DTH) were investigated. Highly purified triglycerides of DGLA (purity>95%) was emulsified with egg-yolk lecithin as a 10% DGLA emulsion.
Mice were injected with 0.5 ml of the DGLA emulsion through tail veins. In the total phospholipid fraction of plasma and spleen cells, DGLA was significantly increased from 1.93±0.43 mol% to 5.56±0.29 mol % in 3 h, and from 1.05±0.05 mol % to 9.40±2.16 mol % in 6 h, respectively.
Mice were immunized with sheep red blood cells (SRBC) . When those mice were intravenously injected with 0.5 ml of the emulsion at the challenge of SRBC, the DTH response measured 24 h later was almost completely suppressed. This suppressive effect of the emulsion was significant with as little as 0.05 ml of the emulsion. A soybean oil emulsion (Intrali-pid^®) was not effective at all.
In conclusion, intravenous injection of the DGLA emulsion increased DGLA concentrations in immune cells in 6 h and reduced the DTH reaction.

View full abstract

Pulmonary fibrosis is characterized by accumulation of alveolar macrophages spontaneously releasing exaggerated amounts of the potent mesenchymal cell growth factor platelet-derived growth factor (PDGF) . To evaluate the contribution of the two PDGF genes to this process, PDGF-A and -B gene transcription rates, mRNA levels and protein levels were examined in alveolar macrophages of normals and individuals with idiopathic interstitial pneumonia (TIP) . While nomal alveolar macrophages constitutively transcribed both PDGF-A and -B genes, LPS stimulation significantly increased the transcription of both genes. Interestingly, TIP alveolar macrophages spontaneously transcribed both genes at a rate similar to that observed for LPS-stimulated normal macrophages. Consistent with the transcription data, normal macrophages contained mRNA for both PDGF-A and-B, but PDGF-B mRNA was 10-fold more abundant. Importantly, in TIP, both PDGF-A and-B mRNA levels were markedly increased, with persistence of the 10-fold dominance of PDGF-B mRNA. Furthermore, the immunohistochemical study demonstrated that TIP macrophages contained increased amounts of PDGF molecules with the 10-fold excess of PDGF-B chain> PDGF-A chain.
Thus, the exaggerated release of PDGF by TIP alveolar macrophages is likely modulated by upregulated PDGF gene transcription rates and concomitantly increased mRNA levels, and most of the PDGF molecules released by the alveolar macrophages are likely PDGF-BB homodimers.

View full abstract

Masugi nephritis in WKY rats was compared with this nephritis in other strains. WKY rats developed severe proliferative glomerulonephritis with massive proteinuria and crescent formation when a small dose of anti-GBM sera was given. Immunohistochemical examination showed that rabbit IgG, but not rat IgG and C3, was stained in a glomerular capillary walls with a linear pattern, and that the infiltration of CD 8 positive cells preceeded the influx of monocytes/macrophages and crescent formation.
These data indicate that CD 8 positive cells play a key role in the accumulation of monocytes/rnacrophages and urinary protein excretion, and subsequent crescent formation.

View full abstract

To evaluate the gastroduodenal mucosal damaging action and its mechanisms of an inactive form of indomethacin farnesil (IND·F) (as a prodrug of indomethacin), compared with placebo, a double blind controlled randomized study was carried out in 19 healthy normal volunteers.
Indomethacin farnesil (IND·F) 400 mg or IND·F placebo twice daily were administered for 2 weeks with an endoscopic assessment on baseline and 14 days after treatment.
Utilizing a previously established criterion of a score 1 or less as a clinically significant degree of protection to the gastroduodenal mucosa, we found that the success rate for IND·F was 25% (2/8), compared to 0% (0/9) for placebo. However, no significant difference was found between IND· F treatment group and placebo administered group. The enhancement of gastric acid secretion and decrease in mucosal blood flow by indomethacin were not observed in both groups.
These findings suggest that IND·F has a low ulcerogenic potency to reduce mucosal damages.

View full abstract

The therapeutic effect of mizoribine (MZR) on spontaneous autoimmune disorders in MRL/Mp-lpr/lpr (MRL/l) mice was investigated. Mice were administered MZR for 3 days a week, orally, from 8 to 20 weeks of age. MZR at a dose of 20 mg/kg had a beneficial effect on the lesions in lupus nephritis and arthritis, histopathologically. At a dose of 40 mg/kg, MZR prevented the appearance of dermatitis, the lymphoproliferation of lymph nodes, reduced serum anti-dsDNA antibody titer, IgG-rheumatoid factor and anti-sheep red blood cells immune response. MZR increased number of both T cells and B cells form rosettes with SRBC. These findings provide evidences that MZR is applicable to human autoimmune diseases.

View full abstract