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Allen P Kaplan

Publications and source records attributed to Allen P Kaplan.

At least 19 recordsLinked to original sources
PubMed2006

Surfactant protein A and D in human sinus mucosa: a preliminary report.

INTRODUCTION: Surfactant-associated proteins (SPs) play a crucial role in the innate defense system and serve as the initial step in the immune response to inhaled pathogens. SP-A and SP-D expression and function are altered in a variety of inflammatory and infectious diseases of the lungs, such as asthma, allergies, and cystic fibrosis, but their presence and function in the sinonasal cavity has not been investigated. The objective of this study was to test our hypothesis that SP-A and SP-D are present in the human sinus. MATERIALS AND METHODS: Sinus mucosal biopsies were performed in 8 patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis, pituitary tumors, and cerebrospinal fluid leak repairs. Expression of SP mRNA and protein by the sinus mucosa was detected by RT-PCR and immunoblot analysis, respectively. RESULTS: Analyses of mucosal biopsies from these patients revealed the presence of SP-A and SP-D mRNA and protein in all specimens. CONCLUSION: SP-A and SP-D are expressed in both normal and diseased human sinus tissue. Understanding the role of SPs in diseased and healthy states may elucidate their possible roles in innate immunity in the upper airway and allow us to develop novel treatments for sinonasal pathologies.

Blotting, Western↗
PubMed2005

Angioedema.

UNLABELLED: Although first described more than 130 years ago, the pathophysiology, origin, and management of the several types of angioedema are poorly understood by most dermatologists. Although clinically similar, angioedema can be caused by either mast cell degranulation or activation of kinin formation. In the former category, allergic and nonsteroidal anti-inflammatory drug-induced angioedema are frequently accompanied by urticaria. Idiopathic chronic angioedema is also usually accompanied by urticaria, but can occur without hives. In either case, an autoimmune process leading to dermal mast cell degranulation occurs in some patients. In these patients, histamine-releasing IgG anti-FcepsilonR1 autoantibodies are believed to be the cause of the disease, removal or suppression by immunomodulation being followed by remission. Angiotensin-converting enzyme inhibitor-induced angioedema is unaccompanied by hives, and is caused by the inhibition of enzymatic degradation of tissue bradykinin. Hereditary angioedema, caused by unchecked tissue bradykinin formation, is recognized biochemically by a low plasma C'4 and low quantitative or functional C'1 inhibitor. Progress has now been made in understanding the molecular genetic basis of the two isoforms of this dominantly inherited disease. Recently, a third type of hereditary angioedema has been defined by several groups. Occurring exclusively in women, it is not associated with detectable abnormalities of the complement system. Angioedema caused by a C'1 esterase inhibitor deficiency can also be acquired in several clinical settings, including lymphoma and autoimmune connective tissue disease. It can also occur as a consequence of specific anti-C'1 esterase autoantibodies in some patients. We have reviewed the clinical features, diagnosis, and management of these different subtypes of angioedema. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of the classification, causes, and differential diagnosis of angioedema, the molecular basis of hereditary and non-hereditary forms of angioedema, and be able to formulate a pathophysiology-based treatment strategy for each of the subtypes of angioedema.

Acute Disease↗
PubMed2005

Functional assessment of pathogenic IgG subclasses in chronic autoimmune urticaria.

BACKGROUND: Chronic urticaria is caused by a complement fixing, IgG antibody directed to the alpha-subunit of the IgE receptor, which is present in 35% to 45% of patients. This autoimmune subgroup can be identified by an autologous skin test or histamine release from human basophils or cutaneous mast cells. However, binding assays do not correlate with these functional assays. We considered the possibility that pathogenic antibody may be present within particular IgG subclasses, which might facilitate development of a binding method that can reliably screen patients. OBJECTIVE: To determine the subclass distribution of IgG antireceptor antibodies on the basis of histamine release, and to assess the possibility that a subclass specific ELISA binding method could be used to screen patients. METHODS: We isolated patient IgG by protein G affinity chromatography and then isolated patient IgG subclasses 1, 2, 3, and 4 by a combination of antibody affinity chromatography and protein A affinity chromatography. The ability of each subclass to activate basophils was assayed by histamine release. RESULTS: Patient IgG subclasses IgG 1 , IgG 3 , and to a lesser degree IgG 4 have antibody capable of activating basophils to release histamine, whereas IgG 2 is inactive. Immunoblot or RAST assay that is subclass-specific does not correlate with histamine release as a result of nonfunctional but binding antibody within IgG subclasses 1, 3, or 4, and complement activation by IgG 1 and IgG 3 . CONCLUSION: Purification of IgG subclasses from patients with chronic urticaria demonstrates functional antibody in IgG 1 and IgG 3 and occasionally IgG 4 . Nonfunctional antibody within IgG 2 plus nonfunctional antibody mixed with functional antibody within IgG 1 , IgG 3 , and IgG 4 and effects of complement are responsible for a lack of correlation of histamine release with binding assays even if subclass-specific.

Autoimmune Diseases↗
PubMed2005

Does C-2 kinin exist?

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Complement C1 Inactivator Proteins↗
PubMed2005

Formation of bradykinin: a major contributor to the innate inflammatory response.

The plasma kinin-forming cascade can be activated by contact with negatively charged macromolecules leading to binding and autoactivation of factor XII, activation of prekallikrein to kallikrein by factor XIIa, and cleavage of high molecular weight kininogen (HK) by kallikrein to release the vasoactive peptide bradykinin. Once kallikrein formation begins, there is rapid cleavage of unactivated factor XII to factor XIIa, and this positive feedback is favored kinetically over factor XII autoactivation. Examples of surface initiators that can function in this fashion are endotoxin, sulfated mucopolysaccharides, and aggregated Abeta protein. Physiological activation appears to occur along the surface of endothelial cells both by the aforementioned contact-initiated reactions as well as bypass pathways that are independent of factor XII. Factor XII binds primarily to cell surface u-PAR (urokinase plasminogen activator receptor); HK binds to gC1qR via its light chain (domain 5) and to cytokeratin 1 by its heavy chain (domain 3) and, to a lesser degree, by its light chain. Prekallikrein circulates bound to HK (as does coagulation factor XI), and prekallikrein is thereby brought to the surface as HK binds. All cell-binding reactions are dependent on zinc ion. Endothelial cells (HUVECs) have bimolecular complexes of u-PAR-cytokeratin 1 and gC1qR-cytokeratin 1 at the cell surface plus free gC1qR, which is present in substantial molar excess. Factor XII appears to interact primarily with the u-PAR-cytokeratin 1 complex, whereas HK binds primarily to the gC1qR-cytokeratin 1 complex and to free gC1qR. Release of endothelial cell heat shock protein 90 (Hsp90) or the enzyme prolylcarboxypeptidase leads to activation of the bradykinin-forming cascade by activating the prekallikrein-HK complex. In contrast to factor XIIa, neither will activate prekallikrein in the absence of HK, both reactions require zinc ion, and the stoichiometry suggests interaction of one molecule of Hsp90 (for example) with one molecule of prekallikrein-HK complex. The presence of factor XII, however, leads to a marked augmentation in reaction rate via the kallikrein feedback as well as to a change to classic enzyme-substrate kinetics. The circumstances in which activation is initiated by factor XII autoactivation or by these factor XII bypasses are yet to be defined. The pathologic conditions in which bradykinin generation appears important include hereditary and acquired C1 inhibitor deficiency, cough and angioedema due to ACE inhibitors, endotoxin shock, with contributions to conditions as diverse as Alzheimer's disease, stroke, control of blood pressure, and allergic diseases.

Amino Acid Sequence↗
PubMed2005

Once-daily fexofenadine treatment for chronic idiopathic urticaria: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Chronic idiopathic urticaria (CIU) can have a profound effect on patients' health and quality of life. OBJECTIVE: To evaluate the efficacy and safety of once-daily dosing of fexofenadine hydrochloride, 180 mg, on CIU. METHODS: This randomized, double-blind, parallel-group, placebo-controlled study consisted of a placebo run-in period followed by a 4-week treatment period. Patients 12 years and older with active CIU were randomized 2:1 to receive once-daily fexofenadine, 180 mg, or placebo. The primary end points were change from baseline in mean daily number of wheals (MNW score) and mean daily severity of pruritus during treatment. Secondary efficacy measures included modified total symptom scores and MNW and pruritus severity scores evaluated weekly and instantaneously at trough drug levels. RESULTS: Patients administered fexofenadine (n = 163) experienced significantly greater improvements in MNW and pruritus severity scores compared with the placebo group (n = 92) (P < .001 for both). Similarly, throughout treatment and at each individual week, the mean reductions in modified total symptom scores were significantly greater in the fexofenadine group (P < or = .005 for all comparisons vs placebo). The mean reductions in instantaneous MNW and pruritus severity scores were greater in patients in the fexofenadine group than in those who received placebo (MNW score: P = .015; pruritus severity score: P < .001). There were no significant differences in the frequency of treatment-emergent adverse events between the 2 treatment groups. CONCLUSIONS: A once-daily dose of fexofenadine hydrochloride, 180 mg, offered effective, well-tolerated relief for the management of CIU.

Adolescent↗
PubMed2005

Assembly, activation, and signaling by kinin-forming proteins on human vascular smooth muscle cells.

Cardiovascular disease is the number one cause of death in the United States. Vascular smooth muscle cells (VSMC) are an important constituent of the vessel wall that can bring about pathological changes leading to vascular disease. Depending on the environment, the function of VSMC can deviate profoundly from its normal contractile role. Despite advances in research, the underlying mechanisms that activate VSMC toward vascular disease are poorly understood. For the first time, we have observed that factor XII and high-molecular-weight kininogen, constituents of the blood plasma, can bind to VSMC in a Zn2+-dependent manner. In the presence of prekallikrein, this assembly of factor XII and high-molecular-weight kininogen on VSMC leads to the activation of prekallikrein to kallikrein with a rapid formation of bradykinin. The amount of bradykinin in the culture medium then decreases, presumably because of the presence of a kininase activity. p44/42 mitogen-activated protein kinase is rapidly phosphorylated in response to in situ-generated or in vitro-added bradykinin and is inhibited by bradykinin antagonist HOE-140. Binding of factor XII to VSMC also results in a concentration-dependent phosphorylation of p44/42 mitogen-activated protein kinase. This early mitogenic signal, which is also implicated in atherogenesis, may change the metabolic and proliferative activity of VSMC, which are key steps in the progression of atherosclerosis.

Bradykinin↗
PubMed2004

Chronic urticaria: pathogenesis and treatment.

Patients previously designated as having chronic idiopathic urticaria are now divided into 2 groups: 40% to 50% with chronic autoimmune urticaria, and the remainder with chronic idiopathic urticaria. Patients in both groups may have concomitant angioedema (approximately 40%). The autoimmune subgroup has an association with antithyroid antibodies and is caused by IgG antibody to the alpha subunit of the IgE receptor (35% to 40%), usually reactive with unoccupied IgE receptors, or IgG antibody to IgE (5% to 10%). Complement activation augments histamine secretion by release of C5a. The IgG subclasses that appear to be pathogenic are IgG(1), IgG(3), and, to a lesser degree, IgG(4), but not IgG(2). Histology of chronic urticaria (both subtypes) reveals a perivascular non-necrotizing infiltrate of CD4(+) lymphocytes consisting of a mixture of T(H)1 and T(H)2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited as a result of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules. Suggested therapy for patients with severe disease involves the use of high-dose hydroxyzine or diphenhydramine when nonsedating antihistamines are ineffective, supplemented by H-2 antagonists and leukotriene antagonists. The most severe patient may require protracted treatment with low-dose alternate-day steroid or cyclosporine. Cyclosporine can be steroid-sparing when side effects are encountered or when use of steroids is relatively contraindicated. Careful monitoring of blood pressure, BUN, creatinine, and urinalysis is required.

Autoantibodies↗
PubMed2004

Alterations in eotaxin, monocyte chemoattractant protein-4, interleukin-5, and interleukin-13 after systemic steroid treatment for nasal polyps.

OBJECTIVE: To determine alterations in Th2 chemokines eotaxin and monocyte chemoattractant protein-4 (MCP-4), and cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13), in nasal polyps (NP) after steroid treatment. STUDY DESIGN: Cytokine/chemokine levels were measured in NP before and after steroid therapy and compared to control sinus mucosa. RESULTS: Twenty-one patients (control = 7, NP = 14) were enrolled. Eotaxin and MCP-4 were significantly higher than control tissue (P = 0.004 and 0.003). All four mediators decreased after steroid treatment (P < 0.03). IL-5 and IL-13 in untreated polyps were not significantly different from controls. Patients showed clinical improvement according to SNOT-20 scores (average presteroid score 19, poststeroid score 13) and endoscopic grading (1.75 each side presteroid, 1.13 poststeroid). CONCLUSIONS: Steroids significantly decreased all cytokine/chemokine levels, but the impact on Th2 chemokines was of a much greater magnitude. SIGNIFICANCE: Novel approaches to block inflammatory mediators, particularly Th2 chemokines, may lead to better control of nasal polyposis in the future.

Adrenal Cortex Hormones↗
PubMed2004

The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin-induced pulmonary fibrosis in rats.

OBJECTIVE: The aim of this study was to investigate the inhibitory effect of dexamethasone on the state of proliferation/apoptosis of the pulmonary inflammatory cells in a rat pulmonary fibrosis model induced by bleomycin. METHODOLOGY: Seventy-five pathogen-free Sprague-Dawley (SD) rats were randomly divided into three groups: control, bleomycin (BLM) and dexamethasone (DXM) groups with 25 rats in each group. Each group was then divided into five subgroups based on time of study (1-, 3-, 7-, 14- and 28-days). BAL fluid was obtained, the cells were counted and a differential was performed. A lower DNA content in apoptotic cells was detected and quantitated by flow cytometry. Haematoxylin and eosin staining was performed to observe the extent of alveolitis and fibrosis of lung tissue; the morphological changes in apoptotic cells were discerned by transmission electron-microscopy and a semi-quantitative assessment of apoptotic cells in lung tissue was performed using in situ TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling). RESULTS: The total number of inflammatory cells and the percentage of neutrophils in BAL fluid in almost every subgroup of the DXM group were significantly lower than those in corresponding subgroups of the BLM group (P < 0.01). The percentages of apoptotic cells in BAL fluid in the 14-day and 28-day subgroups of the DXM group were higher than those in corresponding subgroups of the BLM group (P < 0.05). The peak of alveolitis in the DXM group shifted backward and the extent of fibrosis was less than that in the BLM group. The apoptosis index (AI) of inflammatory cells in each of the DXM subgroups was higher than that in corresponding BLM subgroups except for day 14. CONCLUSION: Dexamethasone can induce apoptosis of pulmonary inflammatory cells and reduce the extent of alveolitis and fibrosis in bleomycin-induced pulmonary fibrosis of rats.

Animals↗
PubMed2004

Interaction of high molecular weight kininogen binding proteins on endothelial cells.

Cell surface proteins reported to participate in the binding and activation of the plasma kinin-forming cascade includes gC1qR, cytokeratin 1 and u-PAR. Each of these proteins binds high molecular weight kininogen (HK) as well as Factor XII. The studies on the interaction of these proteins, using dot-blot analysis, revealed that cytokeratin 1 binds to both gC1qR and u-PAR while gC1qR and u-PAR do not bind to each other. The binding properties of these proteins were further analyzed by gel filtration. When biotinylated cytokeratin 1 was incubated with either gC1qR or u-PAR and gel filtered, a new, higher molecular weight peak containing biotin was observed indicating complex formation. The protein shift was also similar to the biotin shift. Further, immunoprecipitation of solubilized endo-thelial cell plasma membrane proteins with anti-gC1qR recovered both gC1qR and cytokeratin 1, but not u-PAR. Immunoprecipitation with anti-u-PAR recovered only u-PAR and cytokeratin 1. By competitive ELISA, gC1qR inhibits u-PAR from binding to cytokeratin 1; u-PAR inhibits gC1qR binding to a lesser extent and requires a 10-fold molar excess. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.

Binding Sites↗
PubMed2003

High molecular weight kininogen and factor XII binding to endothelial cells and astrocytes.

We have quantitated the binding of high molecular weight kininogen (HK) to human microvascular endothelial cells of lung and dermal origin as well as to astrocytes and compared the results with those reported for human umbilical vein endothelial cells (HUVEC). We also reassessed parameters of binding to HUVEC employing cells in suspension as well as cells attached to the culture plate and report similar numbers of sites varying from 6.96x10(5) to 7.71x10(5) per cell. The present study shows that HK binds with high specificity and affinity to microvascular endothelial cells (Kd = 1.86 to 4.5 nM) compared to HUVEC (Kd = 10.35 nM) but with lower affinity to astrocytes (Kd = 23.73 nM). Human cytokeratin 1, urokinase plasminogen activator receptor and gC1qR were found to be HK binding proteins present at the surface of microvascular endothelial cells and astrocytes analogous to that seen in HUVEC, as assessed by inhibition of binding with antibody to each protein. Lung microvascular endothelial cells had approximately half the number of HK binding sites as HUVEC while dermal micro vascular endothelial cells and astrocytes had only 8-10% of the sites/cell. The affinity of binding to the microvascular endothelial cells was greater than HUVEC, the affinity of binding to astrocytes was considerably less, nevertheless binding to each cell type involves gC1qR, cytokeratin 1 and u-PAR to varying degrees. We also demonstrate, for the first time, that factor XII binds to all of these cell types in a saturable and Zn(+2) dependent manner. Given that factor XII accelerates the interactions among cell surfaces and proteins of the contact activation cascade to generate bradykinin, binding of factor XII (and the prekallikrein-HK complex) may serve as a mechanism by which these proteins are concentrated locally to facilitate their interactions.

Astrocytes↗
PubMed2002

Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII.

Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as the angioedema seen with ACE inhibitors and may contribute to bronchial hyperreactivity in asthma. Formation of bradykinin occurs in the fluid phase and along cell surfaces requiring interaction of factor XII, prekallikrein, and high M(r) kininogen (HK). Recent data suggest that activation of the kinin-forming cascade can occur on the surface of endothelial cells, even in the absence of factor XII. We sought to further define this factor XII-independent mechanism of kinin formation. Both cytosolic and membrane fractions from endothelial cells possessed the ability to catalyze prekallikrein conversion to kallikrein, and activation depended on the presence of HK and zinc ion. We fractionated the cytosol by ion exchange chromatography and affinity chromatography by using corn trypsin inhibitor as ligand. The fractions with peak activity were subjected to SDS gel electrophoresis and ligand blot with biotinylated corn trypsin inhibitor, and positive bands were sequenced. Heat shock protein 90 (Hsp90) was identified as the protein responsible for zinc-dependent prekallikrein activation in the presence of HK. Zinc-dependent activation of the prekallikrein-HK complex also depended on addition of either alpha and beta isoforms of Hsp90 and the activation on endothelial cells was inhibited on addition of polyclonal Ab to Hsp90 in a dose-dependent manner. Although the mechanism by which Hsp90 activates the kinin-forming cascade is not understood, this protein represents the cellular contribution to the reaction and may become the dominant mechanism in pathologic circumstances in which Hsp90 is highly expressed or secreted.

Amino Acid Sequence↗