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.
Fibronectin (Fn), which is released from several kinds of cells including alveolar macrophages (AM), is important in inflammatory reactions in the certain lung diseases such as idiopathic pulmonary fibrosis (IPF). Therefore, information on the mechanisms regulating Fn release from AM may be useful for elucidating the pathogenesis of these diseases and developing therapeutic modalities. We supposed that prostaglandin E2 (PGE2), which is known to modulate cellular functions, might be involved in regulation of Fn release, and, accordingly, we measured the release of Fn and PGE2 from AM from normal volunteers (NV), control patients (CP), and patients with IPF. AM from patients with IPF were found to release more Fn than AM from NV (IPF: 250 +/- 58.8/10(6) cells.24 h, NV: 53.0 +/- 7.3 ng/10(6) cells.24 h) and to release less PGE2 than the latter (IPF: 0.48 +/- 0.12 ng/10(6) cells.24 h, NV:1.35 +/- 0.24 ng/10(6) cells.24 h). A negative correlation was found between the contents of Fn and PGE2 in the culture media of AM from NV, CP, and patients with IPF. Lipopolysaccharide, phorbol myristate acetate, and zymosan suppressed Fn release from AM but stimulated their PGE2 release, and these effects were reversed by indomethacin. Exogenous PGE2 (greater than 1 x 10(-8) M) suppressed Fn release. The albumin-antialbumin complex stimulated Fn release but did not affect PGE2 release. These results indicate that Fn release from AM changed in response to various stimuli, and that PGE2 is important in suppressing Fn release from AM, suggesting a negative feedback mechanism of PGE2 in releasing Fn.
It has been shown that human airway trypsin-like protease (HAT) is localized in human bronchial epithelial cells (HBEC), and trypsin activates protease-activated receptor-2 (PAR-2). Activation of PAR-2 activates G-protein followed by an increase of intracellular free Ca2+, [Ca2+]in. This study was undertaken to clarify whether HAT can activate PAR-2 in HBEC or not. RT-PCR showed that HAT mRNA is expressed in HBEC, and PAR-2 mRNA is the most strongly expressed of the known PARs in HBEC. Both PAR-2 agonist peptide (PAR-2 AP) and HAT increased [Ca2+]in in HBEC in a biphasic fashion; a prompt, sharp increase (peak I) and a sustained low plateau (peak II). PAR-2 AP over 100-200 microM and HAT over 200-300 mU/ml (0.08-0.12 microM) induced both peak I and II, and PAR-2 AP below 100 microM and HAT below 200 mU/ml induced only peak II. Both PAR-2 AP-induced and HAT-induced peak I were induced by Ca2+ mobilization from intracellular stores, because they appeared even in Ca2+-free medium. Both PAR-2 AP-induced and HAT-induced peak II were induced by an influx of extracellular Ca2+, because they were abolished in Ca2+-free medium. The Ca2+ response to HAT was desensitized by exposure of HBEC to PAR-2 AP. These results indicate that HBEC have a functional PAR-2, and HAT regulates cellular functions of HBEC via activation of PAR-2.
A female patient aged of 51 y.o. had been administrated by corticosteroid for treatment of systemic lupus erythematodes and autoimmune hemolytic anemia. She was suffered by cryptococcal meningitis during the steroid therapy. Though the symptoms of meningitis slightly reduced by a therapy with miconazole and flucytosin, the symptoms were found again after 3 months. Then she was treated with 1200 mg/day of ketoconazole. This therapy resulted in abatement of subjected symptoms and sterilization of cerebral spinal fluid. Transient elevation of GOT, GPT, ALP and γ-GPT were observed after 2 months from begining of admisnistration.This case suggestes that therapy with ketoconazole is useful for patients with cryptococcal meningitis who can't be recieved standard therapy with amphotericin B or the combination of amphotericin B plus flucytosine.
To examine the mechanism of tissue damage which causes bronchiolectasis in diffuse pan-bronchiolitis (DPB), the cellular components, elastase and its main inhibitor, alpha 1-protease inhibitor (α1-PI) were measured in bronchoalveolar and bronchial lavage fluid (BALF and BLF) from 14 DPB patients. A predominant increase in the neutrophil count was observed in DPB. Elastase activity in BALF and BLF was about 1, 000-fold higher in the DPB group than in the control group. An inhibitor study and a positive correlation between elastase activity and the neutrophil count in both lavage fluids from the DPB group indicated that the activity was mainly that of neutrophil elastase. Western blot analysis of αl-PI showed that most of the α1-PI in the lavage fluids from DPB group was degraded. These results indicated that neutrophil infiltration increases the level of elastase in the DPB lesions ; this increase seems to be closely related to tissue damage.(Internal Medicine 31 : 599-605, 1992)
The effect of biochemical components on the viscoelasticity of nasal mucus from 24 patients with chronic sinusitis (CS) was investigated by multiple stepwise regression analysis. The dynamic viscosity ( η′ ) and the elastic modulus (G ′ ) of nasal mucus were determined with an oscillating sphere magnetic rheometer at oscillatory frequencies of 1 and 10 Hz. The η′ and G ′ values of mucus determined at 1 Hz were 1.6 ± 1.5 Pa/s and 31.8 ± 31.0 Pa, respectively, and these values were much higher than optimal viscoelasticity for mucociliary transport. The concentrations of fucose, N-acetyl neuraminic acid, albumin, IgG, secretory-IgA, and lysozyme were measured in the same mucus samples. The multiple regression analysis showed that the concentration of fucose, a marker of mucous glycoproteins, was the most important determinant of η′ and G ′ . The analysis also revealed that the level of IgG was the next important determinant. The coefficients of multiple determination for fucose and IgG were 0.732 and 0.733 when the response variables were η′ and G ′ , respectively. The results indicate that locally produced mucous glycoproteins may largely contribute to the high viscoelasticity of nasal mucus in CS.
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