Fibroblasts are important for maintenance of the structural frame network for most tissues, and they also play an important role in the inflammatory process via production of various mediators. In this study, we demonstrated that pulmonary fibroblasts may participate in pulmonary inflammation by production of neutrophil chemotactic factor (NCF). Pulmonary fibroblasts were stimulated with various cytokines (IGF-1, PDGF, IL-1 alpha, IL-1 beta, IL-2, IL-6, TNF, IFNr). Fibroblasts stimulated with either TNF, IL-1 alpha or IL-beta but not IGF, PDGF, IL-2 or IL-6 demonstrated a kinetic and dose-dependent increase in NCF activity. The NCF activity of crude supernatant was heat-stable and was not changed by anti-C5 antibody treatment or ether extraction. Characterization of the NCF activity by gel-filtration using high pressure liquid chromatography showed two active fractions, one with MW greater than 100 kD and the other with MW less than 10 kD. NCF activity in the small molecular weight fraction was demonstrated by inhibition of chemotaxis by addition of anti-IL-8 antibody. These data suggest that cytokine-treated fibroblast-derived NCF may be important in the pathogenesis and expression of a variety of pulmonary disease processes associated with neutrophil accumulation and activation.
Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that, in rats, delamanid was broadly distributed to various tissues in addition to the lungs.
Multiple drug resistant protein 1 (MDR1), P-glycoprotein, plays a role in the blood-brain barrier, preventing drug distribution into the brain, and in cancer chemotherapy. MDR1 is composed of two repeated fragments and there are six transmembrane domain (TMD) on the N-terminal of each repeat and a nucleotide-binding domain (NBD) on the C-terminal. We reported that sera from autoimmune hepatitis patients well reacted with MDR1 by enzyme-linked immuno-sorbent assay (ELISA) [Shinoda et al., (2004) Autoimmunity, 37, 473-480]. In this study, to determine antigenic sites, peptides on the extra-cellular loop (ECL), TMD and NBD of MDR1 were applied to ELISA with sera from 4 autoimmune hepatitis (AIH) patients and 4 normal individuals. The results showed that serum from Patient 3 reacted well with peptide 314-328 and weakly with peptide 957-971. Meanwhile, serum from Patient 4 reacted well with peptide 850-857 and weakly with peptide 741-755 and 957-971. All the five peptides reacted with sera from Patients 3 and 4 were located on ECL. Normal sera did not react with those peptides and the reactions of sera from Patients 1 and 2 were marginal. Sera from 4 patients and normal individuals did not react with peptides of TMD and NBD. These results suggest that some ECL on MDR1 play a role of antigenic determinants, and TMD and NBD do not. Personal specificity and diversity of antibodies from the AIH patients (such as Patients 3 and 4) against antigenic determinant were found.
The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [(3)H]PGE(2) binding to both human and rat EP(4) receptors with K(i) of 13 +/- 4 and 20 +/- 1 nM, respectively. CJ-023,423 is highly selective for the human EP(4) receptor over other human prostanoid receptor subtypes. It also inhibits PGE(2)-evoked elevation in intracellular cAMP at the human and rat EP(4) receptors with pA(2) of 8.3 +/- 0.03 and 8.2 +/- 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE(2) (ED(50) = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.
With the high economic growth of Japan, the life level of the nation has been gradually stabilized. On the other hand, the dietary life made a speedy progress after the war and is further continuing the progress, however, it is said that the rate of malnutrition due to dietary life has not changed even at present. This fact suggests that a correct nutritional diet is not taken. As a point the anemia may be considered.Especially the female anemia has a high percentage in whole Japan and in this prefecture also 60% of person are said anemia. As the start of the study of its origin, the relation of the amount of animal protein taken to hemoglobin and hematocrit is investigated. The subject of investigation is part time agrarian families in the west part of this prefecture, e. d. Tokorozawa City, Asaka City, and Higashi-matsuyama City. Communities in this district are lack of circulation as for the local dietary circumstance.Among female person, 21% are normal and anemic or light anemic person show a high percentage of 79%.The variety of food is somewhat rich in the normal person and the correlation coefficient between the number of food materials and hematocrit is 0.37, which is rather significant valueThe correlation between the classification of animal proteins and hematocrit and/or hemoglobin is not found significant, however, it is observed that the fish protein is not especially superior among animal proteins.
Abstract Acetylations of 2- and 3-methoxy-4H-cyclopenta[def]phenanthrene gave predominantly the 1- and 8-acetyl derivatives, respectively. The acetylation of the 1-methoxy compound afforded the 2-, 3-, 5-, 7-, and 8-yl ketones and the reaction of the 8-methoxy derivative yielded the 1- and 3-acetyl derivatives. Similar reactions of 1-, 2-, 3-, and 8-methoxy-4H-cyclopenta[def]phenanthren-4-one occurred mainly at the 2-, 1-, 8-, and 9-positions, respectively.
To clarify the mechanism of pulmonary fibrosis, the growth rate of fibroblasts obtained from bleomycin (BLM)-treated rats was compared with that of fibroblasts obtained from control rats. Proliferation of fibroblasts obtained from rats at 4 days after BLM instillation (BRF) was significantly more rapid than that of fibroblasts obtained from rats at 4 days after saline instillation (CRF), as assessed by cell counting and 3H-TdR incorporation. CRF and BRF were separated by the method of discontinuous Percoll gradients. Three fibroblast fractions of specific gravity (S.G.), S.G. < 1.036, 1.036 < or = S.G. < 1.050, 1.050 < or = S.G. < 1.062, were obtained. Percentages of the densest fibroblast fraction were 46.2 +/- 5.2 in BRF and 6.4 +/- 2.8 in CRF. The densest fibroblasts in BRF proliferated more rapidly than the least dense fibroblasts. Rat rIL-1 alpha suppressed the proliferation of CRF and BRF, dose dependently. These results suggest that an increase in the densest fibroblasts in the lung might correlate with BLM-induced pulmonary fibrosis and that IL-1 alpha suppresses the proliferation of pulmonary fibroblasts.
In the present genome-wide association study of 2,994 Japanese subjects, rs2071699 (35C>T) in the fucosyltransferase 1 (FUT1) gene was identified as a marker associated with serum alkaline phosphatase (ALP) levels. This gene encodes α(1,2)-fucosyltransferase, which is responsible for the synthesis of H antigens. In a linear regression model incorporating genetic markers, rs550057 (C>T), which is located within an intron of the ABO blood group (ABO) locus, rs2071699 in FUT1 and a gene-gene interaction between these loci accounted for 12.4, 0.9 and 0.3% of the total variability in the serum ALP level, respectively. Further association analysis using imputed genotypes detected rs1047781 in FUT2. rs1047781 is well known in this association with serum ALP levels and showed a moderate linkage with rs2071699 in FUT1. An interaction analysis using rs1047781 in FUT2 also suggested that the interaction with rs550057 in ABO is significant and contributes to the interindividual variance of serum ALP levels as well as rs2071699 in the FUT1 gene. Thus, there is evidence of interactions between ABO and FUT1/FUT2 on serum ALP levels, regardless of the possibility that rs2071699 in FUT1 is a proxy of rs1047781 in FUT2 in the Japanese population.