Four cases of lung cancer associated with idiopathic interstitial pneumonia

It is well known that lung cancer develops frequently in patients with idiopathic interstitial pneumonia (IIP) (9.8-22.8%). We investigated 4 patients who developed lung cancer among the 28 patients with IIP (14.3%) who were admitted to our hospital from June 1981 to March 1989. Many reports have pointed out the clinical features of lung cancer associated with IIP as male sex, old age, heavy smoking, and poor prognosis. Our 4 series were agreed with these clinical features. Lung cancer associated with IIP have been often reported to occur in the lower and peripheral regions of the lung, and honeycomb structures are frequently seen. But we found that lung cancer in IIP could actually occur in both the lower and upper regions of the lung and does not occur only in the honeycomb structures. There was no obvious dominance of any histological type among the tumors. If lung cancer is suspected in a patient with IIP, tumor markers are of some value for diagnosis, but are not sensitive enough to be used alone.     

Bio-adhesio-chemo (BAC) therapy for patients with malignant pleural effusion

Eighteen patients with serious pleuritis carcinomatosa with remarkable pleural effusion were treated with a new pleurodesic therapy, and all the patients treated obtained favorable results. After removing pleural effusion, fibrinogen solution was intrapleurally instilled and then, our newly devised material, G.T.XIII and an anticancer drug, Adriamycin (ADM), were administered as chemosclerosing agents in an attempt to prevent recurrence of the effusion and also to provide locoregional antineoplastic effects. Recurrence of pleural effusion was nil in all patients treated, and subjective complaints of the patients were remarkably relieved. There were 14 patients evaluable, and all the response of these patients resulted in partial response (PR) according to the World Health Organization (WHO) criteria. Improvement of performance status (PS) was observed in 61% (11/18). Eight patients could be discharged. Three patients have remained alive. Fifteen patients died after the therapy, and their median survival was 67 days. Eight patients were autopsied. The postmortem examinations confirmed that fibrous adhesion in the pleural cavity with these materials was significant, and evidence of recurrence of pleural fluid was not seen. Topical oncolytic effects of the ADM were histologically remarkable. This pleurodesis was called "Bio-adhesio-chemo (BAC) therapy."     

Chymase participates in chronic dermatitis by inducing eosinophil infiltration

An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) to a mouse ear caused a transient skin swelling, and the repetition of the challenge enlarged the contact dermatitis. The repeated challenge with DNFB also induced eosinophil infiltration on the application site. Administration of a chymase inhibitor significantly inhibited the ear swelling as well as eosinophil accumulation. An intradermal injection of human chymase to the mouse ear also elicited transient skin swelling and eosinophil infiltration, both of which were augmented in proportion to the number of injections. Human serum albumin and heat-inactivated chymase failed to induce such skin reactions, suggesting the participation of proteolytic activity of the enzyme. In addition, chymase stimulated eosinophil migration in vitro in a concentration-dependent manner. Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration. It is therefore possible that chymase plays a role in pathogenesis of chronic dermatitis such as atopic dermatitis.     

Possible involvement of bcl-2 suppression in wild-type p53 gene-dependent cell growth repression in rat osteosarcoma cells

We recently obtained 3 cloned cell lines demonstrating the p53 mutation from a lung metastatic nodule of a rat transplantable osteosarcoma. In this study, we applied wild-type p53 gene transfer to the rat osteosarcoma cells by lipofection to investigate the effects on cell growth, expression of genes such as waf1/p21, bcl-2, and bax, and nucleosomal DNA fragmentation due to apoptosis. Reconstitution of the p53 gene inhibits cellular growth, and this growth-suppressive effect is partly due to apoptosis involving bcl-2 gene suppression in this tumor type. This rat osteosarcoma model is similar in biologic behavior to human cases and thus is very suitable for further investigation of tumorigenesis and gene therapy for osteosarcoma.     

Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse

The sphingolipid activator proteins (saposins A, B, C and D) are small homologous glycoproteins that are encoded by a single gene in tandem within a large precursor protein (prosaposin) and are required for in vivo degradation of some sphingolipids with relatively short carbohydrate chains. Human patients with prosaposin or specific saposin B or C deficiency are known, and prosaposin- and saposin A-deficient mouse lines have been generated. Experimental evidence suggests that saposin D may be a lysosomal acid ceramidase activator. However, no specific saposin D deficiency state is known in any mammalian species. We have generated a specific saposin D(-/-) mouse by introducing a mutation (C509S) into the saposin D domain of the mouse prosaposin gene. Saposin D(-/-) mice developed progressive polyuria at around 2 months and ataxia at around 4 months. Pathologically, the kidney of saposin D(-/-) mice showed renal tubular degeneration and eventual hydronephrosis. In the nervous system, progressive and selective loss of the cerebellar Purkinje cells in a striped pattern was conspicuous, and almost all Purkinje cells disappeared by 12 months. Biochemically, ceramides, particularly those containing hydroxy fatty acids accumulated in the kidney and the brain, most prominently in the cerebellum. These results not only indicate the role of saposin D in in vivo ceramide metabolism, but also suggest possible cytotoxicity of ceramide underlying the cerebellar Purkinje cell and renal tubular cell degeneration.     

Ultrastructural localization of laminin-5 (gamma2 chain) in the rat peri-implant oral mucosa around a titanium-dental implant by immuno-electron microscopy

Laminin-5 (Ln-5) is an important molecule associated with epithelial cell adhesion and migration. In the gingiva around the tooth, Ln-5 localizes within basement membranes between the junctional epithelium (JE) and the tooth or connective tissue. Recently, we reported that in the oral mucosa around a dental implant, Ln-5 is expressed within the basement membranes at the implant-peri-implant epithelium (PIE) interface, and at the PIE-connective tissue interface. However, the ultrastructural localization of Ln-5 within or along the PIE has not yet been reported. Therefore, peri-implant oral mucosa was treated with anti-Ln-5 (gamma2 chain) antibody and examined using immuno-electron microscopy. Ln-5 was localized in the cells of the innermost-third layer and basal layer of the PIE. A 100-nm-wide Ln-5-positive internal basal lamina (basement membrane) and hemidesmosomes as adhesion structures were formed at the apical portion of the implant-PIE interface. However, at the upper-middle portion of the interface, these adhesion structures were not observed. Furthermore, at the PIE-connective tissue interface, the Ln-5-positive external basal lamina (basement membrane) and hemidesmosomes were partially deficient. Judging from these findings, we concluded that Ln-5 contributes to the attachment of the PIE to the titanium surface, and that PIE attached to titanium at the apical portion of the dental implant-PIE interface.     

A novel bioactive 31-amino acid ET-1 peptide stimulates eosinophil recruitment and increases the levels of eotaxin and IL-5

OBJECTIVE AND DESIGN: Investigation of the role of a novel inflammatory mediator 31-amino acid endothelin-1 [ET-1 (1-31)], a major ET derivative in granulocytes, in eosinophil recruitment after its subcutaneous administration to mice. METHODS: Various ET-1 derivatives (100 pmol), with or without ET receptor antagonists (200 pmol), were administered subcutaneously to mice, and then the eosinophil migration into and chemokine levels in the injected loci were analyzed. RESULTS: ET-1 (1-31) and a 21-amino acid endothelin-1 (ET-1), but not big ET-1, induced eosinophil migration into the injected loci with a peak after administration for 12 h, and increased the levels of eotaxin and interleukin-5 with peaks at 6 and 24 h, respectively. These effects of ET-1(1-31) and ET-1 were significantly inhibited by an ETA receptor antagonist, BQ-123, but not by an ETB receptor antagonist, BQ-788. CONCLUSION: Novel bioactive ET-1 (1-31) induces local eosinophil migration, and increases in eotaxin and interleukin-5 through an ETA or ETA-like receptor.     

IgG inhibits the increase of platelet-associated C3 stimulated by anti-platelet antibodies

We investigated the increase of platelet-associated IgG and complement component 3 (C₃) caused by the in vitro action of anti-platelet MoAbs, and the effect of mouse and human IgG on these events. Anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib MoAbs caused a slight increase of C₃, but not of platelet-associated IgG. In contrast, anti-CD9 and anti-Fcγ II receptor MoAbs caused an increase of both platelet-associated C₃ and IgG. In particular, three MoAbs which activated the complement system caused a marked increase of C₃. When platelet-rich plasma was treated with aspirin and prostaglandin E₁ before incubation with antibodies, the increase of platelet-associated IgG was inhibited in all cases. In contrast, the increase of platelet-associated C₃ was scarcely influenced. These results suggest that the binding to platelets of platelet-activating antibodies caused the increase expression of IgG molecules on the platelet surface and a possible increase of platelet-associated IgG. However, the increase of platelet-associated C₃ appeared to depend on specific characteristics of the antibodies tested, such as a complement-activating effect. In addition, intact mouse or human IgG inhibited the increase of platelet-associated C₃ caused by complement-activating antibodies, while F(ab')₂ mouse or human IgG had no such effect. This suggested that the Fc portion of IgG may block the increase of C₃ mediated by anti-platelet antibodies.