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Biomedical subjects

Lisa A Beck

Publications and source records attributed to Lisa A Beck.

16 recordsLinked to original sources
PubMed2006

Functional analysis of the chemokine receptor CCR3 on airway epithelial cells.

The function of chemokine receptors on structural cells is only partially known. We previously reported the expression of a functional CCR3 receptor on airway epithelial cells (EC). We speculated that CCR3 might drive wound repair and expression of inflammatory genes in epithelium. The human airway EC lines BEAS-2B, 16-HBE, and primary bronchial EC were used to test the effect of in vitro challenge with the CCR3 ligands CCL11/eotaxin, CCL24/eotaxin-2, or CCL26/eotaxin-3 on 1) wound repair, using an established wound model; 2) cell proliferation and chemotaxis, using specific fluorometric assays; and 3) gene expression, using pathway-specific arrays for inflammatory and profibrotic cytokines, chemokines, and chemokine receptor genes. Agonist specificity was tested by cell pretreatment with an AstraZeneca CCR3 antagonist (10(-8) - 10(-6) M). CCL24 challenge significantly accelerated epithelial wound closure, with similar effects exerted by CCL11 and CCL26. This effect was time dependent, submaximal at 1 nM, and comparable in potency to epidermal growth factor. CCL24 induced a concentration-dependent increase in EC proliferation and chemotaxis, with significant effects observed at 10 nM. The AstraZeneca compound selectively inhibited these CCL24-mediated responses. CCL11 induced the up-regulation of several profibrogenic molecules such as fibroblast growth factor 1 and 5 and of several CC and CXC chemokines. Epithelial immunostaining for CCR3 was stronger in bronchial biopsies of asthmatics displaying marked inflammatory changes than in nondiseased samples. Epithelial CCR3 participates in key functions for wound repair, amplifies the expression of profibrogenic and chemokine transcripts, and appears up-regulated in inflamed asthmatic airways.

Cell Line↗
PubMed2006

Increased expression of Th2-associated chemokines in bullous pemphigoid disease. Role of eosinophils in the production and release of these chemokines.

Bullous pemphigoid is an inflammatory disease of the skin associated with eosinophil infiltration and the presence of high levels of Th2 cytokines in the associated blister fluid. Little is known about the contribution of chemokines in this disease. We found that eotaxin and MCP-4 mRNA and immunoreactivity were expressed in all biopsies of BP patients and were mainly localized to the epidermis and eosinophils. The expression of eotaxin and MCP-4 was enhanced in eosinophils following IL-5 treatment. Subsequent stimulation of IL-5-primed eosinophils with Ig-immune complexes, results in increase secretion of eotaxin and MCP-4 in the supernatants. Using immunostaining, these two chemokines were localized to the granules of eosinophils. BF was found to contain chemotactic activity for eosinophils, neutrophils and T cells. The chemotactic effect of BF for eosinophils was more effective when eosinophils were stimulated with IL-5 or IL-4. We also found that the levels of Th(2)-associated chemokines (eotaxin and MCP-4) in BF were significantly higher than the Th(1)-associated chemokines (MIP-1beta and IP-10). This was consistent with the increased chemotaxis of polarized Th(2) cells toward BF, when compared to Th(1)-differentiated T cells. Our results support the involvement of Th(2)-associated chemokines in the pathogenesis of BP disease.

Adult↗
PubMed2006

Innate immune defects in atopic dermatitis.

Atopic dermatitis (AD) is a common, chronic inflammatory skin disease that becomes clinically apparent in the pediatric population. It is well recognized that subjects with AD have an increased susceptibility to cutaneous colonization and infection with bacteria, fungi, and viruses. The notion that subjects with AD have a cutaneous immune defect has received widespread acceptance, and several plausible explanations for this have been proposed. We will review the evidence that this susceptibility to cutaneous infection is at least in part due to a defect in the first line of defense against microbes, namely the innate immune system.

Dermatitis, Atopic↗
PubMed2006

Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes.

BACKGROUND: The gene encoding acyloxyacyl hydroxylase (AOAH), an enzyme that hydrolyzes secondary fatty acyl chains of LPS, is localized on chromosome 7p14-p12, where evidence for linkage to total IgE (tIgE) concentrations and asthma has been previously reported. OBJECTIVE: We hypothesized that variants in AOAH are associated with asthma and related phenotypes. Because both AOAH and soluble CD14 respond to LPS, we tested for gene-gene interaction. METHODS: We investigated the association between 28 single nucleotide polymorphisms throughout the AOAH gene and asthma, concentrations of tIgE, the ratio of IL-13/IFN-gamma, and soluble CD14 levels among 125 African Caribbean, multiplex asthmatic pedigrees (n = 834). Real-time PCR was used to assess whether AOAH cDNA expression differed with AOAH genotype. RESULTS: Significant effects were observed for all 4 phenotypes and AOAH markers in 3 distinct regions (promoter, introns 1-6, and the intron 12/exon 13 boundary/intron 13 region) by means of single-marker and haplotype analyses, with the strongest evidence for a 2-single-nucleotide-polymorphism haplotype and log[tIgE] (P = .006). There was no difference in AOAH expression levels by AOAH genotype for any of the markers. Comparing genotypic distributions at both the AOAH marker rs2727831 and CD14(-260)C >T raises the possibility of gene-gene interaction (P = .006-.036). CONCLUSION: Our results indicate that polymorphisms in markers within the AOAH gene are associated with risk of asthma and associated quantitative traits (IgE and cytokine levels) among asthmatic subjects and their families in Barbados, and there is an interactive effect on tIgE and asthma concentrations between an AOAH marker and the functional CD14(-260)C >T polymorphism. CLINICAL IMPLICATIONS: AOAH is a novel innate immunity candidate gene associated with asthma and related phenotypes in an African ancestry population.

Asthma↗
PubMed2006

Successful treatment of recalcitrant chronic idiopathic urticaria with sulfasalazine.

BACKGROUND: Antihistamines are the standard treatment for chronic idiopathic urticaria (CIU). For patients whose urticaria is unresponsive to antihistamines, the treatment options are limited. During the previous decade, there have been several case reports demonstrating success with sulfasalazine therapy. In this article, we present a case series evaluating sulfasalazine therapy for antihistamine-unresponsive CIU. OBSERVATIONS: Nineteen patients with antihistamine-unresponsive CIU were treated with sulfasalazine between 2002 and 2005. During sulfasalazine therapy, 14 patients (74%) reported significant improvement, 4 patients (21%) reported minimal improvement but were not satisfied with their symptom relief, and 1 patient (5%) reported a worsening of symptoms. Of the 13 patients who required systemic steroids to control their urticaria, all were able to reduce or discontinue steroid use during sulfasalazine therapy. Although 7 patients (37%) had adverse effects (eg, nausea, headache, mild or transient leukopenia, and transaminitis) that were thought to be caused by the use of sulfasalazine, they all kept taking the drug. CONCLUSIONS: This case series demonstrates that sulfasalazine can be a successful and safe treatment option for patients with CIU who have not responded adequately to treatment with antihistamines. Sulfasalazine was steroid sparing in all subjects who were steroid dependent.

Adolescent↗
PubMed2006

Emerging therapeutic options for atopic dermatitis: beyond TIMs.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts both patients and their families. Although current therapies provide relief of symptoms for most but not all patients, they do not prevent or eradicate the disease. In this new era of biological therapy, medications that precisely target the molecular mediators of inflammation are being developed at a rapid pace. These biologic agents have proven useful for treating many inflammatory illnesses, as well as providing insight into disease pathogenesis. In atopic dermatitis, these new therapies may prove highly useful to both treat and prevent the disease. In this review article, we briefly review the pathogenesis of AD to discuss current therapies and to introduce potential new treatments.

Anti-Inflammatory Agents↗
PubMed2005

The efficacy and safety of tacrolimus ointment: a clinical review.

Topical tacrolimus ointment was approved for the treatment of atopic dermatitis in Japan in 1999, the United States in 2000, and Europe in 2001. The safety and efficacy of tacrolimus ointment was established in vehicle-controlled, randomized, 12-week clinical trials; 1-year open-label trials; and comparative studies with topical steroids. Although an extensive database exists on the safety and efficacy of tacrolimus ointment based on the global development program, clinicians desire additional information on the long-term safety and efficacy of this novel agent. In this supplement, additional studies are reported that extend the safety and efficacy profile of tacrolimus ointment in patients with atopic dermatitis, including long-term safety studies for up to 4 years. The studies presented in this supplement address important questions regarding the selection and use of tacrolimus ointment in the treatment of patients with atopic dermatitis.

Clinical Trials as Topic↗
PubMed2005

Chemokines: key players in innate and adaptive immunity.

Healthy individuals initiate an immediate immune response to microbes by using a set of germline-encoded receptors that recognize common molecular patterns found on the surface of pathogens that are distinct from self-antigens. This innate immune response is the first line of defense against microorganisms in vertebrates, and constitutes the only immune response in plants and invertebrates. The innate immune system includes cellular components, as well as a host of soluble products (antimicrobial peptides, complement fragments, cytokines, and chemokines). The adaptive immune response, which provides long-lasting protection, takes days to develop and requires somatic mutations leading to the development of antigen-specific T cell receptors (cell-mediated immunity) and immunoglobulins (humoral immunity). Members of the chemokine superfamily are crucially involved in both innate and adaptive responses. We review the biological actions of the chemokine superfamily, focusing on several functions that are relevant for both immune responses, such as cell recruitment, microbicidal activity, cell activation, polarization of CD4+ T cells, and effects on structural cells. In particular, we will illustrate the central role that chemokines play in host defense, best demonstrated by the tremendous number of chemokine and chemokine receptor homologs found in microbial genomes, which deflect the immune response of the host.

Animals↗
PubMed2004

Activation of airway epithelial cells by toll-like receptor agonists.

Toll-like receptors (TLR) play an important role in pathogen recognition and innate immunity. We investigated the presence and function of TLRs in the BEAS-2B airway epithelial cell line and primary bronchial epithelial cells. Standard real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and Taqman RT-PCR revealed that BEAS-2B cells express mRNA for TLR1-10. Several TLR ligands were tested for their ability to activate gene expression in BEAS-2B cells using limited microarray analyses focusing on genes of the chemokine and chemokine receptor family, cytokines, and signaling pathways. While the TLR3 ligand double-stranded RNA was the most effective epithelial activator, clear responses to flagellin, lipopolysaccharide, CpG, peptidoglycan, and zymosan were also observed. RT-PCR and/or enzyme-linked immunosorbent assay were used to confirm results obtained with microarrays for five of the induced genes: interleukin-8, serum amyloid A, TLR3, macrophage inflammatory protein-3alpha, and granulocyte-macrophage colony-stimulating factor. Stimulation of epithelial cells with double-stranded RNA induced levels of interleukin-8 exceeding 20 ng/ml and levels of serum amyloid A exceeding 80 ng/ml. Double-stranded RNA, lipopolysaccharide, zymosan A, and flagellin also induced expression of macrophage inflammatory protein-3alpha and granulocyte-macrophage colony-stimulating factor, which may facilitate immature dendritic cell migration and maturation. These results suggest that airway epithelial cells express several TLRs and that they are functionally active. Epithelial expression of TLRs may be of importance in inflammation and immunity in the airways in response to inhaled pathogens.

Allergens↗
PubMed2004

Keratinocytes in atopic dermatitis: inflammatory signals.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that usually predates the development of allergic airway disease. In most cases, this is thought to be an allergen-driven disease with prominent roles played by antigen presenting cells and effector Th2 cells. But keratinocytes, by virtue of their location, provide an important window to the environment and are also thought to contribute to the development of AD. In this review, we discuss several biologic attributes of keratinocytes that are relevant for AD: 1) intrinsic defects in barrier function, 2) production of inflammatory mediators that promote or maintain allergic inflammation, 3) keratinocyte apoptosis, 4) effects of staphylococcal toxins on keratinocytes, and 5) potential consequences of the expression of cosignaling molecules (eg, B7 family members) and receptors important for innate immune responses (eg, Toll receptors). Clearly, these findings have highlighted a more active role played by the epithelium than was previously recognized.

Apoptosis↗
PubMed2004

Omalizumab-induced reductions in mast cell Fce psilon RI expression and function.

BACKGROUND: By design, omalizumab binds free IgE in the circulation and prevents its attachment to the surface of mast cells and basophils, thereby preventing them from responding to allergens. Previously, omalizumab rapidly reduced free IgE levels, as well as basophil high-affinity IgE receptors, leading to significant reductions in basophil mediator response to allergen. It is assumed that tissue mast cells are similarly altered in their Fc epsilon RI density and function. OBJECTIVE: We examined the phenotypic shift of skin mast cells in parallel to that of blood basophils in 3 subjects infused with omalizumab. METHODS: Three subjects with allergic rhinitis underwent intradermal skin test titration with house dust mite antigen at days 0, 7, 70, and 196 of omalizumab treatment. As control subjects, 5 untreated subjects with allergic rhinitis were evaluated at similar time points. All subjects underwent skin biopsy 18 to 24 hours later at the site of allergen injection. Biopsy specimens were characterized by means of immunohistochemisty for tryptase and Fc epsilon RI alpha immunoreactivity, as well other markers (CD3, CD45RO, CD68, cutaneous lymphocyte antigen, and major basic protein). RESULTS: Omalizumab recipients, but not control subjects, demonstrated reductions in Fc epsilon RI alpha immunoreactivity at days 70 and 196 in parallel with reductions in the acute wheal response to allergen. However, no reductions in tryptase-positive cells were noted at these time points. CONCLUSION: Reductions in free IgE levels by omalizumab leads to a rapid reduction in basophil Fc epsilon RI receptor expression. In contrast, the time course for the decrease of Fc epsilon RI expression in skin mast cells is slower and associated with decreased acute allergen wheal size.

Allergens↗
PubMed2003

Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.

BACKGROUND: IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. OBJECTIVE: We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. METHODS: We performed an open-label trial of anti-IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. RESULTS: Anti-IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti-IL-5. In addition, anti-IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti-IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. CONCLUSIONS: These results suggest that anti-IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti-IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.

Adolescent↗
PubMed2003

Atopic dermatitis and asthma: parallels in the evolution of treatment.

OBJECTIVES: To review epidemiologic correlations between asthma and atopic dermatitis (AD), identify common features in disease pathophysiology, and review steps involved in the development of asthma therapy guidelines to assess the appropriateness of a similar process and approach for AD. METHODS: A 7-member panel representing specialists in dermatology, allergy, asthma, immunology, and pediatrics from around the United States convened to review the current literature and evolving data on AD. Participants presented reviews to the panel on the epidemiology of asthma and AD, the genetic predisposition to allergic disease, the current understanding of the immunopathophysiology of AD, interrelationships between the pathologic pathways of asthma and AD, evolving treatment concepts and options in AD, and the applicability of the asthma treatment model and how it may be adapted for guideline development for AD. Commentary and criticism were recorded for use in document preparation. RESULTS: There are clear epidemiologic parallels in asthma and AD. Importantly, AD frequently is the first manifestation of an atopic diathesis, which occurs in genetically predisposed individuals and also includes asthma and allergic rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis or asthma later in childhood. This classic "atopic triad" has numerous pathophysiologic elements in common, including cyclic nucleotide regulatory abnormalities, immune cell alterations, and inflammatory mediators and allergic triggers. New therapeutic options that target underlying immune mechanisms are available, and their place among treatments for AD is becoming established. Guidelines of care have been developed for asthma. The panel noted that the National Institutes of Health/National Heart, Lung, and Blood Institute guidelines for diagnosis and management of asthma, first issued in 1991, had a tremendous positive impact on many aspects of asthma treatment. It not only created a heightened awareness that asthma is a disease of chronic inflammation, but it also provided unified approaches for therapy and opened new areas of basic science and clinical research. In addition, the guidelines spurred interactions among physicians of various specialties and stimulated a great quantity of research in asthma therapy. It is anticipated that AD therapy guidelines would have similar positive outcomes. CONCLUSIONS: The panel concluded that, on the basis of current information and evolving therapeutic options, a clear rationale exists to support AD guideline development. The many parallels between AD and asthma suggest that processes and approaches used for the asthma therapy guidelines would be appropriate for AD.

Administration, Topical↗
PubMedDate not supplied

Cancer rehabilitation: does it make a difference?

Cancer is a significant cause of physical and cognitive disability. The concept of cancer rehabilitation was developed in the 1970s; it was a concept that led to funding support and to significant contributions to symptom management. A recent trend has been an increase in the number of cancer diagnoses and an increase in cancer survival rate. This suggests that more persons with cancer are living longer despite cancer-caused impairments. Interdisciplinary cancer rehabilitation programs are designed to help cancer patients achieve maximal functional ability and adapt to disabilities resulting from cancer or its treatments. Currently, there are few cancer rehabilitation programs in the United States. Information about the role of rehabilitation nursing in cancer patient care is scarce. The purposes of this article were to review the history of cancer rehabilitation; review functional outcomes that have been reported in current research; and identify the multiple, complex challenges that illustrate the role of a cancer rehabilitation clinical nurse specialist in the rehabilitation of cancer patients.

Adult↗