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Biomedical subjects

E Corsini

Publications and source records attributed to E Corsini.

At least 73 records · Page 4Linked to original sources
PubMed1995

In vitro keratinocytes responses to chemical allergens.

An early event during the induction of skin sensitization is the production by keratinocytes (kc) of cytokines. Considering the role of kc in skin inflammatory and immune responses, we investigated the effect of three skin allergens (oxazolone, nickel sulfate and mixture of methyisothiazolinone and methylcholoisothiazolone) on IL-1 alpha production by a murine kc cell line (HEL30). Confluent cells were treated for different times with various concentrations of oxazolone, NiSO4 and mixture of methyisothiazolinone and methylcholoisothiazolone. IL-1 alpha was measured by ELISA both in conditioned media and cell-associated. All chemicals were able to induce a dose-response production of IL-1 alpha. This increase was related to an increase in protein synthesis as measured by 3H-leucine incorporation. At high concentrations all chemicals were cytotoxic as measured by LDH release. In the same cell system we also measured the effect of lanolin, a non irritant compound, on IL-1 alpha release. Even at the concentration of 300 micrograms/ml no IL-1 alpha release could be detected in the conditioned media. We have previously found a good rank correlation between in vitro surfactants induced IL-1 alpha release and in vivo Draize test. We now extend the possibility to use IL-1 alpha production for preliminary screening of chemicals for their irritative/allergenic potential, reducing the need for in vivo models.

Allergens↗
PubMed1994

Asbestos stimulates IL-8 production from human lung epithelial cells.

Studies have indicated that soluble products, including chemotactic factors, released by activated lung macrophages and fibroblasts are critical mediators in the pathogenesis of asbestos-induced pulmonary fibrosis. We provide evidence that mediators produced by lung epithelial cells in response to asbestos may also contribute to lung disease. In the present study, the carcinogenic and fibrogenic fibers, chrysotile and crocidolite asbestos, were shown to directly stimulate the human pulmonary type-II epithelial cell line, A549, and to a lesser degree primary human bronchial epithelial cells, to elicit the chemotactic cytokine IL-8 in the absence of endogenous stimuli such as IL-1 and TNF. That the membrane signaling events responsible for asbestos-induced IL-8 production are distinct from those responsible for IL-8 induction by cytokines was confirmed by using membrane-stabilizing agents and protein synthesis inhibitors. Stimulation was not observed with nonfibrogenic fibers, wollastonite and titanium dioxide, and was the direct result of asbestos-induced initiation of transcription. Asbestos failed to stimulate the release of TNF, IL-1 beta, or monocyte chemoattractant protein-1 in A549 or primary bronchial epithelial cells, indicating that cytokine secretion by asbestos is highly selective. However, a slight release of IL-1 alpha, probably preformed, was released in human bronchial epithelial cells. These data suggest that epithelial cells may, in addition to macrophages and fibroblasts, be an important effector cell in the immunopathogenesis of asbestos-associated diseases and in particular, in the neutrophilic infiltration that is commonly observed after asbestos exposure.

Asbestos, Serpentine↗
PubMed1994

A protective role for T lymphocytes in asbestos-induced pulmonary inflammation and collagen deposition.

Several lines of evidence have suggested that specific (i.e., lymphocyte) immunity plays a role in chemical-induced pulmonary diseases, including asbestosis. To evaluate the influence of cell-mediated immunity in pulmonary inflammation and fibrosis evoked by asbestos fibers, we compared the effects of asbestos in immunodeficient mice (Balb/c nu/nu and severe combined immunodeficient [C3H-SCID]), immunologically normal mice of the same genetic background, and immunodeficient mice reconstituted with syngeneic T lymphocytes. Increases in lavaged cell numbers occurred in asbestos-treated immunodeficient mice compared with asbestos-treated immunocompetent or immunodeficient mice that received T lymphocytes. Differential analysis of the collected cells in treated mice demonstrated a predominantly neutrophilic infiltrate that correlated with increased levels of leukotriene B4 and prostaglandin E2. There were no significant differences between immunocompetent and athymic asbestos-treated mice in bronchoalveolar lavaged total protein. However, asbestos-treated SCID mice revealed a significant increase in protein content and lactate dehydrogenase activity compared with asbestos-treated normal mice, which did not occur in T lymphocyte-reconstituted SCID mice. Fibronectin levels were elevated in asbestos-exposed athymic mice when compared with air-exposed athymic mice or asbestos-exposed immunocompetent mice. Both asbestos-treated athymic and SCID mice showed a significant increase in total lung hydroxyproline when compared with asbestos-treated immunocompetent mice. Lung hydroxyproline was also reduced in asbestos-exposed SCID mice after T lymphocyte reconstitution and, conversely, increased in T cell-depleted Balb/c mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests.

We have reported on the design and content of a screening battery using a "tier" approach for detecting potential immunotoxic compounds in mice (Luster et al., Fundam. Appl. Toxicol., 10, 2-19, 1988). The data base generated from these studies, which consists of over 50 selected compounds, has been collected and analyzed in an attempt to improve future testing strategies and provide information to aid in developing future quantitative risk assessment for immunotoxicity. In a recent study it was shown that as few as two or three immune parameters were needed to predict immunotoxicants in mice (Luster et al., Fundam. Appl. Toxicol., 18, 200-210, 1992). In particular, enumeration of lymphocyte populations and quantitation of the T-dependent antibody response were particularly beneficial. Furthermore, commonly employed apical measures (e.g., leukocyte counts, lymphoid organ weights) were fairly insensitive. The present analyses focus on the use of this data base to develop statistical models that examine the qualitative and quantitative relationship(s) between the immune function and host resistance tests. The conclusion derived from these analyses are: (1) A good correlation exists between changes in the immune tests and altered host resistance in that there were no instances where host resistance was altered without affecting an immune test(s). However, in some instances immune changes occurred without corresponding changes in host resistance. (2) No single immune test could be identified which was fully predictive for altered host resistance, although most assays were relatively good indicators (i.e., > 70%). Several others, such as proliferative response to lipopolysaccharide and leukocyte counts, were found to be relatively poor indicators for host resistance changes. (3) The ability to resist infectious agent challenge is dependent upon the degrees of immunosuppression and the quantity of infectious agent administered. (4) Logistic and standard regression modeling using one extensive chemical data set from the immunosuppressive agent, cyclophosphamide, indicated that most immune function-host resistance relationships followed linear rather than linear-quadratic (threshold-like) models. For most of the relationships this could not be confirmed using a large chemical data set and, thus, a more mechanistically based approach for modeling will need to be developed. (5) Using this limited data set, methods were developed for modeling the precise quantitative relationships between changes in selected immune tests and host resistance tests.

Animals↗
PubMed1992

Pentamidine blocks the pathophysiologic effects of endotoxemia through inhibition of cytokine release.

Pentamidine isethionate, an antiprotozoal agent with therapeutic value against Pneumocystis carinii pneumonia, has been used for over 30 years without a precise understanding of its mechanism of pharmacologic action. We have previously reported that pentamidine has the capacity to inhibit the release of cytokines from macrophages through a post-translational processing event. The present studies were undertaken to assess the ability of pentamidine to modulate the detrimental effects of murine endotoxemia, a disease with a pathophysiology clearly linked to host-produced cytokines. Under conditions where normal B6C3F1 mice succumbed to the lethal effects of endotoxin, mice pretreated with pentamidine were significantly protected from both mortality and loss of thermoregulatory control. The EC50 for protection from mortality by pentamidine was approximately 11.4 mg/kg. These observations correlated with decreased serum levels of tumor necrosis factor (TNF) and interleukin 6. Inhibition of cytokines was not manifested as part of a generalized inhibition of protein synthesis as demonstrated by the lack of significant modulation of serum albumin in pentamidine-treated animals. In addition to decreased serum concentrations of cytokines, lungs isolated from mice treated with both pentamidine and endotoxin exhibited a decreased release of TNF compared to lungs isolated from mice treated with vehicle and endotoxin. The lower levels of TNF released from lung tissue in pentamidine-treated mice correlated with a lesser degree of alveolar deterioration than was observed in vehicle-treated mice. These data indicate that following endotoxin administration, pentamidine has a protective and antiinflammatory role both systemically and in the lung and suggest that inhibition of inflammatory cytokines may be one mechanism operable in the therapeutic activity of the drug against P carinii pneumonia.

Animals↗
PubMed1992

Pneumocystis carinii induction of tumor necrosis factor-alpha by alveolar macrophages: modulation by pentamidine isethionate.

Pneumocystis carinii, and the inflammatory response it provokes, together contribute to irreversible lung damage in immunocompromised patients. P. carinii cysts were found to be capable of inducing tumor necrosis factor-alpha (TNF) release from alveolar macrophages in a concentration-dependent manner. At physiologically achievable concentrations, pentamidine isethionate (pentamidine) substantially reduces such production. Pretreatment of alveolar macrophages (AM phi) with interferon-gamma (IFN-gamma) synergizes with P. carinii to produce increased levels of TNF, a condition which pentamidine was also able to antagonize. Pentamidine treatment did not interfere with the phagocytic ability of AM phi. Considering clinical reduction of TNF could lessen P. carinii pneumonia (PCP) induced inflammation, the efficacy of pentamidine in the treatment of PCP may be partially associated with its ability to inhibit the release of inflammatory mediators such as TNF.

Animals↗
PubMed1992

Modulation of tumor necrosis factor release from alveolar macrophages treated with pentamidine isethionate.

Alveolar macrophages in AIDS patients have a marked increase in tumor necrosis factor release in active Pneumocystis carinii pneumonia. We have demonstrated that pentamidine, an aromatic diamidine currently used to treat AIDS-related P. carinii pneumonia, is an effective inhibitor of cellular tumor necrosis factor release from lipopolysaccharide-stimulated rat alveolar macrophages at concentrations greater than 10(-8) M. Inhibition of release is not dependent upon the continued presence of pentamidine in the culture medium during the release phase. In addition, this blockage occurs at neither the transcriptional level as determined by Northern blot analysis nor the translational level as determined by Western blot analysis. Timed addition studies suggest that pentamidine is targeting relatively early events following lipopolysaccharide administration. Pentamidine appears to alter early lipopolysaccharide-induced cellular processes associated with the release of tumor necrosis factor from macrophages.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Two dimensional gel electrophoresis of cellular and secreted proteins from rat alveolar macrophages after lipopolysaccharide treatment.

Two dimensional gel electrophoresis (2-D PAGE) and automated image analysis were used to study the effects of bacterial lipopolysaccharide (LPS) activation on secreted and cellular rat alveolar macrophage proteins. Primary alveolar macrophages were cultured and exposed to LPS in the presence of [35S]-methionine for 24 h. Image analysis of 2-D PAGE revealed that LPS treatment primarily modulated the proportions of several alveolar macrophage cellular proteins versus control in addition to limited protein induction and repression. The differential effect of LPS was more pronounced on secreted proteins where qualitative and quantitative differences from control cells were found. Immunoblots of secreted proteins with anti-tumor necrosis factor alpha (TNF alpha) and anti-interleukin-1 alpha(IL-1 alpha) antibodies identified these monokines from protein fluorographic patterns. IL-1 alpha was detected as a single polypeptide of 17 kD at pI = 5. Use of recombinant TNF alpha and monoclonal and polyclonal antibodies for immunodetection revealed the 17 kD form of TNF alpha as well as higher molecular weight species at 18 kD and 22 kD. Thus, analysis of radiolabeled rat macrophages treated with LPS reveals quantitative modulation of several cellular proteins as well as a distinctive pattern of secreted proteins which contain multiple monokine forms resolvable by 2-D PAGE.

Animals↗
PubMed1991

Pentamidine isethionate reduces Ia expression and antigen presentation by Langerhans cells and inhibits the contact hypersensitivity reaction.

The mechanism of action of pentamidine isethionate, a diamidino compound used in the treatment of Pneumocystis carinii pneumonia, is unknown. We recently reported that this drug may inhibit the release of inflammatory mediators from alveolar macrophages, which may be associated with its antiparasite activity. As a potential anti-inflammatory agent, we report that topically applied pentamidine reduces ear swelling in the contact hypersensitivity reaction to oxazolone in B6C3F1 mice. The application of pentamidine must occur within 1 h, at the challenge site, to be effective. Topical application appears necessary, because i.v. injection had no effect on reduction of ear swelling. In dose-response studies, a 50% reduction in ear swelling was achieved with as little as 20 micrograms of pentamidine. Pentamidine did not affect Ag transport from the challenge site to the draining lymph nodes, as measured by FITC transport. However, there was a 30 to 40% reduction in epidermal cells expressing Ia Ag from pentamidine-treated mouse ears, compared with control. Ia expression is almost exclusively limited to Langerhans cells in the normal epidermis. This reduction in Ia expression was not due to simple depletion of Langerhans cells by pentamidine, because CD45 expression was unaffected. Concurrent with reduced Ia expression, Ag presentation by pentamidine-treated Langerhans cells was also reduced. Taken together, a mechanism of action for pentamidine in inhibition of the contact hypersensitivity reaction appears to be via a reduction in Ag presentation by decreasing Ia+ Langerhans cells.

Animals↗
PubMed1991

Pentamidine: an inhibitor of interleukin-1 that acts via a post-translational event.

Pharmacologic inhibition of cytokines, particularly interleukin-1 (IL-1), potentially has numerous therapeutic applications in inflammatory diseases. We demonstrate that pentamidine, an aromatic diamidine currently used to treat Pneumocystis carinii pneumonia, is a specific and effective inhibitor of cellular IL-1 release from macrophages, and we have shown that this blockage occurs at neither the transcriptional nor the translational level. Pentamidine induced inhibition of IL-1 occurs via an alteration in the post-translational modification of the protein, altering the intracellular and/or membrane cleavage of the 31-kDa pro-IL-1 to the 17-kDa secreted form. In addition, pentamidine exhibited less broad immunosuppressive actions when compared to a corticosteroid, the classical therapeutics utilized for inhibition of cytokine production.

Animals↗
PubMed1991

Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino acid mixtures.

The hypothesis that incorporation of tryptophan (TRY) into proteins is the mechanism underlying the decrease in plasma and tissue TRY levels after a TRY-free amino acid mixture was investigated. Rats fasted 15 hours were pretreated with saline or with the protein synthesis inhibitor cycloheximide (CHEX) and treated with saline or a TRY-free amino acid mixture. In a first experiment, in saline pretreated rats the TRY-free mixture caused a decrease of 49% in total plasma TRY, of 64% in free plasma TRY, of 66% in brain TRY and of 42% in liver TRY. After 5 mg/kg of CHEX the same TRY-free diet caused a decrease of 5% in total plasma TRY, 14% in free plasma TRY, 18% in brain TRY and 9% in liver TRY. In a second experiment, the TRY-free diet caused a 43% decrease of total plasma TRY in saline pretreated animals and a decrease of 15%, 6% and 2% respectively after the pretreatment with 0.3, 1.0 and 5.0 mg/kg of CHEX. In brain TRY, the TRY-free diet caused a 62% decrease in saline pretreated rats and a decrease of 38%, 20% and 19% respectively after the pretreatment with 0.3, 1.0 and 5.0 mg/kg of CHEX. Since 5.0 mg/kg of CHEX almost completely block protein synthesis and since doses of CHEX from 0.3 to 5.0 mg/kg cause a dose-dependent inhibition of protein synthesis, our data support the hypothesis that protein synthesis is the mechanism through which TRY-free mixtures decrease TRY levels.

Amino Acids↗
PubMed1990

Different effects of TPA on two skin-derived cell lines: murine (HEL-30) and human (NCTC) epidermal cells.

12-O-tetradecanoylphorbol-13-acetate (TPA) caused a rapid activation of protein kinase C in a murine (HEL-30) and in a human (NCTC) epidermal cell line. In HEL-30 cells, protein kinase C activation is followed by ornithine decarboxylase stimulation and cell proliferation, events inhibited by H-7, a specific inhibitor of protein kinase C. TPA in NCTC cells inhibited the basal ornithine decarboxylase activity and cell growth, whereas H-7 did not modify TPA effect. The response of NCTC cells was not due to direct toxicity of TPA. These data confirm that in murine epidermal cells, the proliferation induced by TPA is mediated by protein kinase C, whereas in a human skin-derived cell line these events are not or inversely associated.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Evaluation of the oral toxicity of spinacine hydrochloride in a 13-week study in rats.

Spinacine (4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), the major reaction product of formaldehyde added to Grana Padano cheese, was administered to five groups of ten rats of each set at dietary concentrations that provided doses of O (control), 15, 30, 60 or 300 mg/kg body weight/day for 13 wk. There were no adverse effects upon survival, growth or food intake. No significant treatment-associated changes were found in haematological parameters, in serum chemistry or organ weights at the end of the study. At autopsy, neither gross nor histological modifications were attributable to treatment with spinacine. In this study the no-effect dose level for spinacine was considered to be 300 mg/kg body weight/day.

Administration, Oral↗
PubMedDate not supplied

Selective stimulation of cutaneous interleukin 6 expression by skin allergens.

Epidermal cells, both keratinocytes and Langerhans cells, are able to synthesize and secrete a variety of cytokines, many of which influence or are essential for the induction of skin sensitization and the elicitation of local inflammatory reactions. It has been proposed that it may prove possible to distinguish between contact allergens and skin irritants as a function of differential induction or upregulation of epidermal cytokine expression. In the present study we have addressed this by examination of the local cutaneous production of interleukin 6 (IL-6) following topical exposure of mice to oxazolone, a potent contact allergen, or to benzalkonium chloride (BZC), a skin irritant that is considered not to have a significant potential to cause skin sensitization. Both oxazolone and BZC could induce the production of IL-6 as measured by enzyme-linked immunosorbent assay in homogenates prepared from treated skin. However, when these chemicals were applied at concentrations that resulted in equivalent cutaneous inflammatory responses, based on induced oedema, only oxazolone provoked the production in skin of IL-6. Moreover, under these conditions exposure only to oxazolone resulted in the secretion by draining lymph node cells of measurable concentrations of this cytokine. These data suggest that the ability of oxazolone to stimulate local IL-6 production is not secondary simply to the induction of local inflammatory responses. As such, the results support the possibility that skin allergens and skin irritants may stimulate variable patterns of epidermal cytokine production.

Adjuvants, Immunologic↗
PubMedDate not supplied

Postnatal ontogenesis of dopaminergic and serotoninergic systems in rat caudate nucleus.

The development and sex differences of the catecholaminergic and serotoninergic systems were studied in rat caudate nucleus by measuring dopamine, serotonin and their metabolites in male and female pups from birth up to day 30 of life. Dopamine increased regularly during the entire period studied, while its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), increased sharply only after day 9 of life. At birth, serotonin levels were 50% of the juvenile value; its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), increased greatly after day 6 of life. No difference was observed in male and female neurotransmitter ontogenesis. The results indicated that dopaminergic and serotoninergic systems were not mature in the caudate nucleus at birth. A functional immaturity of enzyme systems involved in neurotransmitter synthesis and/or catabolism is suggested.

Animals↗
PubMedDate not supplied

Asbestos toxicity: an immunologic perspective.

Asbestos has long been associated with a number of life threatening pulmonary diseases, including asbestosis and mesothelioma. While the lung is the primary target organ for asbestos toxicity, a number of clinical and experimental studies over the past 30 years have shown that the immune system may also be altered by exposure to asbestos at occupationally relevant concentrations. Whereas early clinical studies generally focused on systemic observations of immune alteration, more recent studies have assessed the immunological changes occurring in the lung, the primary target organ of asbestos. This review will focus on the investigations that examine the influence of asbestos on systemic and local immunity, as well as the role that the immune system may play in asbestos-related disease.

Antibody Formation↗
PubMedDate not supplied

[Determination of interleukin-8 in induced sputum of workers exposed to low concentrations of asbestos].

The concentration of interleukin-8 (IL-8) in the induced sputum of 17 workers exposed to low airborne asbestos levels and of 10 controls was determined. IL-8 levels were statistically significantly increased in the asbestos exposed group compared to controls. This finding underlines the usefulness of the study of proinflammatory mediators as possible predictors of alveolar damage.

Asbestos↗