S L Madison

Research Triangle Park Laboratories, Inc., Raleigh, North Carolina, United States

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Publications (5)35.13 Total impact

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    ABSTRACT: Metarhizium anisopliae, an entomopathogenic fungus, is a prototypic microbial pesticide licensed for indoor control of cockroaches, a major source of allergens. We have previously demonstrated allergy and asthma-like responses in BALB/c mice intraperitoneally (IP) sensitized in the presence of adjuvant and intratracheally (IT) challenged with the soluble factors from M. anisopliae crude antigen (MACA) ( and ). This protocol has been used frequently to establish animal models of allergenicity. However, the sensitization protocol is artificial and not representative of an environmental exposure. Concern has been raised that this protocol might produce allergic responses that would not occur under normal environmental exposure conditions. The objective of this study was to compare responses in mice to MACA by two exposure protocols: (1) exclusive respiratory exposures without adjuvant (representative of environmental exposures) and (2) intraperitoneal sensitization in the presence of adjuvant followed by IT challenge (the traditional approach). The intratracheal protocol consisted of four IT exposures of 10 μg MACA in 50 μl HBSS each over a 4-week period. A vehicle control group of mice was exposed IT to HBSS. The intraperitoneal protocol consisted of IP sensitization with 25 μg MACA in 0.2 ml of 1.3% alhydrogel (aluminum hydroxide) followed 14 days later with an IT challenge (10 μg MACA/50 μl HBSS). Airway reactivity responsiveness to methacholine was assessed, serum and bronchoalveolar lavage fluid (BALF) samples were obtained, and the lungs were fixed for histopathology at 1, 3, and 8 days following the last MACA IT challenge. Both groups exhibited immune and pulmonary responses typical of allergic asthma. In general, local responses in the lung, including inflammatory responses (eosinophils, lymphocytes, and macrophages), BALF IgE, and functional responses to methacholine were greater in the IT sensitized group compared to the IP sensitized group, whereas the systemic IgE response was greater in the IP sensitized group. The BALF IL-5 cytokine levels were elevated before and throughout the eosinophil influx. IL-4 was detected in the BALF of IP sensitized, but not IT sensitized mice. Histopathologic changes in the two groups were similar in nature but more severe in the IT mice. The results suggest that the IP sensitization protocol does not induce the level of respiratory responsiveness that results from sensitization by a physiologically relevant route of exposure. Thus total serum IgE levels, which were greater following IP sensitization, may not be the best indicator of allergen potency, at least with respect to respiratory responses.
    Toxicology 07/2000; · 4.02 Impact Factor
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    ABSTRACT: Metarhizium anisopliae is an entomopathogenic fungus recently licensed for indoor control of cockroaches, a major source of allergens. While M. anisopliae has been shown to be non-infectious and non-toxic to mammals there has been only limited research on potential allergenicity. Using a mouse model, we previously demonstrated allergic immune and inflammatory responses to this agent. The present study was designed to determine whether these responses were associated with changes in pulmonary responses, lung pathology, and the cytokine profile in bronchoalveolar lavage fluid (BALF). Soluble factors from fungal components were combined in equal protein amounts to form M. anisopliae crude antigen (MACA). BALB/C mice were intratracheally (IT) challenged with 10 μg MACA 14 days post intraperitoneal sensitization with 25 μg fungal antigen in aluminum hydroxide adjuvant. Physiological and cellular changes were examined. The mice were tested for airway hyperresponsiveness before (No Chal) and after (1, 3, and 8 days post challenge (DPIT)) MACA IT challenge. Subsequently, serum, BALF and the lungs were harvested. All treatment groups concurrently demonstrated significant non-specific pulmonary inflammation (neutrophil influx) and increased pulmonary sensitivity to methacholine (Mch) at 1 DPIT MACA challenge. Where as both adjuvant treated and naı̈ve mice airway responses had returned to near normal levels by 3 DPIT, mice which were previously sensitized with MACA were still hyperresponsive to Mch challenge at 3 and 8 DPIT. This hyperresponsiveness correlates with eosinophil and lymphocyte influx, which is maximal at 3 DPIT and still elevated at 8 DPIT. Interleukin (IL) 5 was elevated for all treatment groups at 1 DPIT but only the MACA sensitized mice maintained elevated levels for both 3 and 8 DPIT. Furthermore, MACA sensitized mice had a more extensive inflammatory histopathology at all examined time points with peribronchial and perivascular infiltrates, like those associated with allergic responsiveness, peaking at 3 DPIT. These pulmonary pathologic changes appeared to be consistent with elevated levels of serum and BALF total IgE, BALF IL-4, eosinophils, and lymphocytes following MACA IT challenge in MACA sensitized mice. There were no significant differences among the three treatment groups with regard to BALF interferon (IFN) γ. The cytokines profiled indicate a Th2-type response, which is reflected in the cellular influx and total IgE induction. These data further indicate that immune inflammatory responses, observed in mice following MACA sensitization and challenge, are associated with physiologic changes and histopathology characteristic of allergic disease.
    Toxicology 03/2000; · 4.02 Impact Factor
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    ABSTRACT: Particulate matter (PM) air pollution may increase symptom severity in allergic asthmatics. To examine possible interaction, or greater than additive responses, between PM effects and allergic responses, an ovalbumin-sensitized and challenged (OVA) mouse model of allergic airways disease was utilized. After challenge, mice were intratracheally instilled with saline vehicle or 3 mg/kg (approximately 60 microg) residual oil fly ash (ROFA), a transition metal-rich emission source PM sample. Physiological and inflammatory responses were examined 1, 3, 8, and 15 d later. In response to intravenously administered methacholine, ROFA increased total respiratory system resistance and decreased compliance 1 d after exposure, whereas effects of OVA lasted at least 15 d after exposure. Significant interactions between OVA and ROFA were mainly observed 8 d after challenge and exposure, especially with respect to compliance. A strong interaction (p < 0.01) between OVA and ROFA exposure resulted in 8-fold (1 d) and 3-fold (3 d) increases in bronchoalveolar lavage (BAL) fluid eosinophil numbers. A similarly strong interaction (8-fold) was observed in BAL fluid interleukin-4 (IL-4) 1 d after challenge and exposure. Significant though less strong interactions were also found with respect to IL-4 and IL-5 by 3 d postchallenge/exposure. This study shows that allergen challenge and exposure to emission source particulate matter containing relatively high levels of transitions metals can interact to increase Th2 cytokine production, eosinophil recruitment, and airway hyperresponsiveness in previously sensitized mice.
    American Journal of Respiratory and Critical Care Medicine 01/2000; 160(6):1897-904. · 11.04 Impact Factor
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    ABSTRACT: To investigate the function of prostaglandin H synthase-1 and synthase-2 (PGHS-1 and PGHS-2) in the normal lung and in allergic lung responses, we examined allergen-induced pulmonary inflammation and airway hyperresponsiveness in wild-type mice and in PGHS-1(-/-) and PGHS-2(-/-) mice. Among nonimmunized saline-exposed groups, we found no significant differences in lung function or histopathology, although PGE(2) was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PGHS-1(-/-) mice, relative to wild-type or PGHS-2(-/-) mice. After ovalbumin sensitization and challenge, lung inflammatory indices (BAL cells, proteins, IgE, lung histopathology) were significantly greater in PGHS-1(-/-) mice compared with PGHS-2(-/-) mice, and both were far greater than in wild-type mice, as illustrated by the ratio of eosinophils in BAL fluid (8:5:1, respectively). Both allergic PGHS-1(-/-) and PGHS-2(-/-) mice exhibited decreased baseline respiratory system compliance, whereas only allergic PGHS-1(-/-) mice showed increased baseline resistance and responsiveness to methacholine. Ovalbumin exposure caused a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE(2) in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE(2) in the normal mouse lung; (b) PGHS-1 and PGHS-2 products limit allergic lung inflammation and IgE secretion and promote normal lung function; and (c) airway inflammation can be dissociated from the development of airway hyperresponsiveness in PGHS-2(-/-) mice.
    Journal of Clinical Investigation 10/1999; 104(6):721-32. · 12.81 Impact Factor
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    ABSTRACT: The biological effects of particulate matter (PM) deposition in the airways may depend on aqueousleachable chemical constituents of the particles. The effects of two residual oil fly ash (ROFA) PM samples of equivalent diameters but different metal and sulfate contents on pulmonary responses in Sprague-Dawley rats were investigated. ROFA sample 1 (R1) had approximately twice as much saline-leachable sulfate, nickel, and vanadium, and 40 times as much iron as ROFA sample 2 (R2), while R2 had a 31-fold higher zinc content. Four groups of rats were intratracheally instilled with a suspension of 2.5 mg R2 in 0.3 ml saline (R2), the supernatant of R2 (R2s), the supernatant of 2.5 mg R1 (R1s), or saline only. By 4 days after instillation, 4 of 24 rats treated with R2s or R2 had died, compared with non treated with R1s or saline, and pathological indices were greater in both R2 groups compared with the R1s group. In surviving rats, baseline pulmonary function parameters and airway hyperreactivity to acetylcholine challenge were significantly worse in R2 and R2s groups than in the R1s group. Numbers of bronchoalveolar lavage neutrophils, but not other inflammatory cells or biochemical parameters of lung injury, were greater in both R2 groups compared with the R1s group. These results reinforce the hypothesis that the composition of soluble metals and sulfate leached from ROFA, an emission source particle, is critical in the development of airway hyperreactivity and lung injury.
    Environmental Research 03/1997; 72(2):162-72. · 3.24 Impact Factor