Biomedical subjects

Paul S Foster

Publications and source records attributed to Paul S Foster.

46 records · Page 3Linked to original sources

PubMed2002

Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease.

For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (T(H)2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key T(H)2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the T(H)2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.

Humans↗

PubMed2002

Interleukin-5 and eosinophils as therapeutic targets for asthma.

Extensive clinical investigations have implicated eosinophils in the pathogenesis of asthma. In a recent clinical trial, humanized monoclonal antibody to interleukin (IL)-5 significantly limited eosinophil migration to the lung. However, treatment did not affect the development of the late-phase response or airways hyperresponsiveness in experimental asthma. Although IL-5 is a key regulator of eosinophilia and attenuation of its actions without signs of clinical improvement raises questions about the contribution of these cells to disease, further studies are warranted to define the effects of anti-IL-5 in the processes that lead to chronic asthma. Furthermore, eosinophil accumulation into allergic tissues should not be viewed as a process that is exclusively regulated by IL-5 but one in which IL-5 greatly contributes. Indeed, data on anti-IL-5 treatments (human and animal models) are confounded by the failure of this approach to completely resolve tissue eosinophilia and the belief that IL-5 alone is the critical molecular switch for eosinophil development and migration. The contribution of these IL-5-independent pathways should be considered when assessing the role of eosinophils in disease processes.

Animals↗

PubMed2002

CD4(+) T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma.

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4(+) T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4(+) T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin-synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4(+) T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.

Allergens↗

PubMed2002

Eotaxin expression by epithelial cells and plasma cells in chronic asthma.

Chemoattractants such as eotaxin are believed to play an important role in the recruitment of eosinophils into the airways in asthma. We investigated expression of eotaxin in the airway wall in a model of chronic human asthma, in which systemically sensitized mice were exposed to low mass concentrations of aerosolized antigen for 6 weeks. In these animals, the number of intraepithelial eosinophils in the airways was significantly increased 3 hours after exposure and declined by 24 hours. In parallel, immunoreactivity for eotaxin was strikingly up-regulated in airway epithelial cells and in inflammatory cells in the lamina propria. The latter were identified as plasma cells by double immunofluorescent labeling. Increased expression of eotaxin by epithelial cells and plasma cells was also demonstrated in a case of fatal human asthma. In contrast, sensitized mice that received a single exposure to a high mass concentration of aerosolized antigen exhibited delayed eosinophil recruitment, which did not correlate with eotaxin expression. Furthermore, in sensitized chronically exposed interleukin-13-deficient mice there was virtually no recruitment of eosinophils into the airways, although eotaxin expression was greater than or equal to that in wild-type mice. These results indicate that there are striking differences between acute and chronic exposure models in the time course of eotaxin expression and eosinophil recruitment. Although high eotaxin levels alone are not sufficient to cause recruitment of eosinophils into the airways, recurrent exposure may generate or up-regulate additional signals required for eosinophil chemotaxis.

Allergens↗

PubMed2002

The relationship between magnitude of cerebral activation and intensity of emotional arousal.

There is considerable knowledge concerning the cerebral localization of positive and negative emotions; however, relatively little is known about the cerebral representation of subjective emotional intensity. Indeed, few studies to date seem to have been conducted on the cerebral effects of increased emotional intensity. The purpose of the present investigation was to investigate the relationship between the intensity of cerebral activation and emotional arousal using quantitative electroencephalography (QEEG). Participants were asked to recollect an angry memory while QEEG was recorded from 19 electrode sites arranged according to the International 10/20 System. Significant positive correlations were found between subjective intensity of angry memories and changes in low beta (13-21 Hz) and high beta (21-32 Hz) magnitude (microV) at the F8, T6, and O1 electrode sites among the male participants. Additionally, a significant positive correlation between emotion intensity and changes in high beta at the T6 electrode site was found among female participants. Results are discussed in terms of implications for emotional regulation and dysfunction.

Adolescent↗

PubMed2002

Experimental analysis of eosinophil-associated gastrointestinal diseases.

Eosinophil infiltration into the gastrointestinal tract occurs in a wide range of diseases. However, the underlying cellular and molecular mechanisms involved in eosinophil migration and the role of eosinophils in disease pathogenesis are largely unknown. Recent studies using experimental models of eosinophil-associated gastrointestinal allergy have revealed differential roles for IL-5 and eotaxin in the modulation of eosinophil accumulation into various regions of the gastrointestinal tract. Furthermore, such studies have revealed a possible role for eosinophils in the pathogenesis of gastrointestinal disorders. The present review describes the clinical manifestations of various eosinophil-associated gastrointestinal disorders and the current understanding of the role of IL-5 and eotaxin in the allergic inflammatory response, and the participation of the eosinophilic granulocyte in the expression of disease.

Animals↗

PubMed2002

Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation.

Zn may have an important protective role in the respiratory epithelium and Zn deficiency may enhance airway inflammation and epithelial damage. The effects of mild nutritional Zn deficiency on airway hyperresponsiveness (AHR) and airway inflammation in mice sensitized and challenged with ovalbumin (OVA) to induce an allergic response were investigated. Balb/c mice were given Zn normal (ZN, 50 mg/kg Zn) or Zn limited diets (ZL, 14 mg/kg Zn) before and during induction of allergic airway inflammation, with appropriate controls (saline-treated, SAL). ZL mice had greater levels of AHR than ZN mice, regardless of presence or absence of allergic inflammation. These mice also had increased eosinophilia and mucus cell hyperplasia compared with ZN mice. Second, ZN and ZL OVA-treated mice had significant decreases in airway epithelial Zinquin fluorescence, indicating a lowered availability of Zn compared with their SAL-treated counterparts. In contrast, the pro-apoptotic protein caspase-3, which was co-localized with Zn in the apical epithelium, was significantly increased in both ZN and ZL OVA-treated mice. Immunologically active caspase-3 and apoptosis were increased in OVA-treated mice, especially the ZL group. These findings provide the first data for adverse effects of Zn deficiency on the respiratory epithelium and support a role for altered Zn homeostasis and caspase upregulation in asthma.

Animals↗

PubMed2002

Modeling allergic asthma in mice: pitfalls and opportunities.

Studies in murine experimental models have contributed greatly to understanding the mechanisms of allergic inflammation underlying asthma. However, models involving short-term high-level exposure of sensitized animals to antigen have significant limitations for investigating the pathogenesis of the lesions of chronic asthma. Modeling chronic asthma is problematic, because long-term antigenic challenge often triggers widespread pulmonary parenchymal inflammation or leads to eventual downregulation of inflammation and airway hyperreactivity. We have developed an improved murine model in which animals are exposed to low mass concentrations of aerosolized antigen for 6-8 wk. The mice exhibit airway-specific acute-on-chronic inflammation and changes of airway wall remodeling as seen in human asthma, together with hyperreactivity to a cholinergic agonist which can be specifically attributed to airway disease. This more realistic model of asthma offers a number of opportunities for investigation of pathogenetic mechanisms and novel therapeutic agents.

Allergens↗

PubMed2002

The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses.

Virus infection presents a significant challenge to host survival. The capacity of the virus to replicate and persist in the host is dependent on the status of the host antiviral defense mechanisms. The study of antiviral immunity has revealed effective antiviral host immune responses and enhanced our knowledge of the diversity of viral immunomodulatory strategies that undermine these defences. This review describes the diverse approaches that are used by RNA viruses to trick or evade immune detection and response systems. Some of these approaches include the specific targeting of the major histocompatibility complex-restricted antigen presentation pathways, apoptosis, disruption of cytokine function and signaling, exploitation of the chemokine system, and interference with humoral immune responses. A detailed insight into interactions of viruses with the immune system may provide direction in the development of new vaccine strategies and novel antiviral compounds.

Adult↗

PubMed2001

Enterocyte expression of the eotaxin and interleukin-5 transgenes induces compartmentalized dysregulation of eosinophil trafficking.

Eosinophils accumulate in the gastrointestinal tract in a number of medical disorders, but the mechanisms involved are largely unknown. To understand the significance of cytokine expression by enterocytes, enterocyte transgenic mice that overexpressed the eosinophil-selective cytokines eotaxin and interleukin (IL)-5 were generated. Transgenic mice, generated by utilizing the rat intestinal fatty acid-binding protein promoter (Fabpi), overexpressed the mRNA for these cytokines in the small intestine. Overexpression of IL-5 resulted in marked increases of eosinophils in the bone marrow and blood, whereas eotaxin overexpression resulted in similar levels compared with nontransgenic control mice. In contrast, both IL-5 and eotaxin transgenic mice had significant accumulation of eosinophils in the gastrointestinal mucosa compared with control mice. Eotaxin-induced gastrointestinal eosinophilia was substantially higher than that induced by IL-5 and was especially prominent within the lamina propria of the villi. Interestingly, genetic rescue of eotaxin deficiency (by transgenic overexpression of eotaxin in eotaxin gene-targeted mice) resulted in significant restoration of gastrointestinal eosinophil levels. Finally, the intestinal eosinophilia induced by the eotaxin transgene was beta(7) integrin-dependent. Taken together, these results demonstrate that expression of eotaxin and IL-5 in intestinal epithelium induces compartmentalized dysregulation of eosinophil trafficking and the important role of the beta(7) integrin in gastrointestinal allergic responses.

Animals↗