Biomedical subjects

D Spina

Publications and source records attributed to D Spina.

At least 19 recordsLinked to original sources

PubMed2006

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis.

The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved.

Cell Cycle↗

PubMed2006

Immunohistochemical co-localization of transient receptor potential vanilloid (TRPV)1 and sensory neuropeptides in the guinea-pig respiratory system.

Electrophysiological studies within the lung have documented the presence of heterogenous groups of afferent fibers composed of Adelta and C-fibers and studies of somatosensory nerves within the skin reveal a complex pattern of distribution of sensory neuropeptides and transient receptor potential vanilloid (TRPV)1 positive nerves. However, the anatomical location of these different subpopulations of nerves within the lung has not been extensively studied. In the present study we have demonstrated that TRPV1 axons represented only a small proportion of the total number of PGP9.5 staining nerves within guinea-pig tracheal epithelium and only half the number of TRPV1 axons was immunopositive for substance P. In contrast, most TRPV1 positive neurones found within guinea-pig intrapulmonary airways were found to co-localize with sensory neuropeptides substance P and calcitonin gene-related peptide within and beneath the epithelium, around blood vessels, within airway smooth muscle and alveoli, indicative of heterogeneity of TRPV1 positive axons throughout the airways. However, in the smooth muscle layer of the trachea there was evidence of substance P and calcitonin gene-related peptide containing nerves that did not stain for TRPV1. We also demonstrated a complete loss of TRVP1 positive axons in the trachea and intrapulmonary airways and associated loss of bronchoconstriction induced by capsaicin, in animals chronically treated with capsaicin. However, some neuropeptide immunoreactive axons remained in the smooth muscle layer of capsaicin-treated animals which could represent the small subset of neuropeptide containing fibers which do not co-localize with TRPV1. We have provided evidence of heterogeneity of TRPV1 positive nerve fibers, including fibers characterized by lack of co-localization with neuropeptides in various regions of the airways and the existence of neuropeptide containing fibers that were not TRPV1 positive in guinea-pigs.

Animals↗

PubMed2004

Effect of Mycobacterium tuberculosis chaperonins on bronchial eosinophilia and hyper-responsiveness in a murine model of allergic inflammation.

BACKGROUND: Epidemiological evidence suggests that infection with Mycobacterium tuberculosis protects children against asthma. Several laboratories have shown that, in mouse models of allergic inflammation, administration of the whole live tuberculosis vaccine, Mycobacterium bovis bacillus Calmette-Guerin (BCG), prevents ovalbumin (OVA)-induced pulmonary eosinophilia. OBJECTIVE: The aim of this study was to characterize specific M. tuberculosis molecules that are known to modulate immune responses to see if they affected pulmonary eosinophilia and bronchial hyper-responsiveness. METHODS: C57Bl/6 mice were sensitized to OVA on days 0 and 7 and subsequently challenged with OVA on day 14 over a 3-day period. Pulmonary eosinophilia and bronchial hyper-responsiveness were measured 24 h following the last antigen challenge. In some groups, mice were pre-treated with M. tuberculosis or M. tuberculosis chaperonins (Cpns)60.1, 60.2 and 10, and the effect of this treatment on the allergic inflammatory response to aerosolized OVA was established. RESULTS: We show that M. tuberculosis Cpns inhibit allergen-induced pulmonary eosinophilia in the mouse. Of the three Cpns produced by M. tuberculosis, Cpn60.1, Cpn10 and Cpn60.2, the first two are effective in preventing eosinophilia when administered by the intra-tracheal route. Furthermore, the increase in airways sensitivity to inhaled methacholine following OVA challenge of immunized mice was suppressed following treatment with Cpn60.1. The allergic inflammatory response was also characterized by an increase in Th2 cytokines IL-4 and IL-5 in bronchoalveolar lavage fluid, which was also suppressed following treatment with Cpn60.1. CONCLUSION: These data show that bacterial Cpns can suppress eosinophil recruitment and bronchial hyper-responsiveness in a murine model of allergic inflammation.

Animals↗

PubMed2003

A comparison of the pharmacological modulation of hyperalgesia and bronchial hyperresponsiveness.

It has been proposed that there may be similarities in the mechanisms contributing toward hyperalgesia/allodynia observed in various clinical pain syndromes and bronchial hyperresponsiveness (BHR) in asthma. Both features are characterized by an increase in responsivity to various stimuli. In the case of pain, these include increase in responsiveness to mechanical and thermal stimuli whilst asthmatics bronchoconstrict in response to substances that are otherwise innocuous. A variety of mediators can induce hyperalgesia and pain when injected into the skin and these same mediators are also released during an inflammatory insult in the airways and in many cases can induce hyperresponsiveness experimentally. In this review, a comparison of the pharmacological modulation of afferent activity in hyperalgesia and in BHR will be made to ascertain whether any commonality exists between the treatment of these two disease states.

Adrenergic alpha-Agonists↗

PubMed2002

Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation.

Over the last decade there has been an intense interest in the potential role of cytokines and chemokines as important mediators in various atopic diseases, including asthma and the mechanisms by which these mediators regulate airway inflammation and bronchial hyperresponsiveness. This research effort has recently culminated in the publication of clinical studies that have assessed the role of interleukin (IL)-4 [Borish et al., Am J Respir Crit Care Med 160, 1816-1823 (1999)], IL-5 [Leckie et al., Lancet 356, 2144-2148 (2000)], and IL-12 [Bryan et al., Lancet 356, 2149-2153 (2000)] in allergic asthma, and the results have been disappointing. This is not surprising given the pleiotropic role cytokines play in the allergic response confirmed by numerous animal studies providing evidence of functional redundancy. The alternative view is that our current concepts in asthma pathogenesis need significant revision. This review will summarise the evidence for the role of cytokines and chemokines in various aspects of asthma pathophysiology; namely, bronchial hyperresponsiveness, eosinophil recruitment to the airways, mucus secretion, and airway remodelling.

Bronchial Hyperreactivity↗

PubMed2002

Dose-related effects of formoterol on airway responsiveness to adenosine 5'-monophosphate and histamine.

Inhaled short-acting beta2-agonists provide greater protection against airway responsiveness (AR) to the mast-cell stimulus, adenosine 5'-monophosphate (AMP), than to histamine, a direct spasmogen. Both terbutaline and albuterol exhibit this mast-cell stabilizing property in a dose-dependent manner. A single dose of the long-acting beta2-agonist formoterol has also been reported to have a mast cell-stabilizing effect, whereas salmeterol has not. To explore the dose-related actions of the long-acting beta2-agonist formoterol on AR, the authors compared the acute effects of three doses of formoterol and terbutaline on AR to AMP and histamine. In a double-blind, randomized, placebo-controlled, cross-over study, 25 mild, steroid naive, asthmatic subjects attended on 10 occasions. At each visit, subjects inhaled either a single dose of terbutaline (500 microg), formoterol (6, 12 or 24 microg) or a matched placebo, administered via Turbuhaler, 30 min prior to challenge with both AMP and histamine. Each dose of beta2-agonist reduced AR to AMP and histamine. The bronchoprotective effects of formoterol (6 microg) and terbutaline (500 microg) were similar in magnitude in reducing AR to histamine (mean +/- SD: 3.6 +/- 0.3 and 3.1 +/- 0.3 doubling doses (DD)) and AR to AMP (3.5 +/- 0.5 and 3.3 +/- 0.4 DD, respectively). Overall, formoterol reduced AR to both spasmogens in a dose-dependent manner. In addition, formoterol (12 and 24 microg) provided a significantly greater protective effect against AMP than against histamine challenge. It decreased AR by 5.7 +/- 0.6 and 6.3 +/- 0.7 DD against AMP and 4.3 +/- 0.4 and 4.8 +/- 0.43 DD against histamine, respectively. The results of this study indirectly demonstrated an in vivo dose-dependent mast-cell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle. This property of beta2-agonists may have clinical benefits in asthma management.

Adenosine Monophosphate↗

PubMed2001

Relationship of airway responsiveness with airway morphometry in normal and immunized rabbits.

Airway responses to chemical stimuli occur over a wide range of concentrations, with overlap between severe, moderate and mild asthmatic groups and with normal healthy individuals. Mathematical modelling has suggested that relative thickness of the airway wall may account for this range of responsiveness. We have investigated whether in vivo airway responsiveness varies as a function of airway wall thickness in terms of airway smooth muscle area in normal and immunized New Zealand White (NZW) rabbits. Airway responsiveness to inhaled methacholine (MCh) was determined in vivo under neuroleptanalgesia. Subsequently, ex vivo responsiveness to MCh (pD(2)=-log EC(50)) of isolated bronchi from the same animal was established. Smooth muscle area per mm basement membrane (SM/mmBM) was also measured morphometrically in the tested bronchi and the findings related to in vivo and ex vivo responsiveness. We found no relationship between airway responsiveness in vivo and pD(2)values in either immunized or control rabbits. In both control and immunized rabbits, no correlation was found between SM/mmBM and in vivo airway responsiveness. Only in immunized animals with a PCA titre >0, was there a significant correlation (=-0.5986, P<0.05) between SM/mmBM and pD(2). We conclude that airway smooth muscle area per se is not the sole contributor of airway responsiveness in vivo in normal rabbits.

Animals↗

PubMed2001

The endogenous cannabinoid agonist, anandamide stimulates sensory nerves in guinea-pig airways.

The endogenous cannabinoid agonist, anandamide produced a modest contractile response in guinea-pig isolated bronchus compared with the vanilloid receptor agonist capsaicin. The contractile response to both anandamide and capsaicin was inhibited by the vanilloid receptor antagonist, capsazepine. Furthermore, the NK(2)-selective antagonist, SR48968 but not the NK(1)-selective antagonist, SR140333 inhibited contractile responses to anandamide. The contractile response to anandamide was abolished in tissues desensitized by capsaicin. However, anandamide failed to cross-desensitize the contractile response to capsaicin. The contractile response to anandamide was not significantly altered in the presence of the CB(1) receptor antagonist, SR141716A, nor the amidase inhibitor, phenylmethylsulphonyl fluoride (PMSF) but was significantly increased in the presence of the neutral endopeptidase inhibitor, thiorphan. The cannabinoid agonist, CP55,940 failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) response in guinea-pig airways. In contrast, the ORL(1) receptor agonist, nociceptin, significantly inhibited this response. The results demonstrate that anandamide induces a modest contractile response in guinea-pig isolated bronchus that is dependent upon the activation of vanilloid receptors on airway sensory nerves. However, cannabinoid receptors do not appear to play a role in this regard, nor in regulating the release of neuropeptides from airway sensory nerves under physiological conditions.

Animals↗

PubMed2001

Protective effect of a PAR2-activating peptide on histamine-induced bronchoconstriction in guinea-pig.

1. Protease activated receptor-2 (PAR2) is a seven transmembrane domain G protein coupled receptor proteolytically activated. PAR2, together with other PARs, can be also activated by peptides mimicking the sequence of the receptor tethered ligand. We have evaluated the effect of systemic administration of a peptide activating PAR2 (PAR2-AP, SLIGRL) on histamine-induced increase in lung resistances in the guinea-pig. 2. Intravenous administration of PAR2-AP (1 mg kg(-1)) significantly inhibited histamine-induced increase in lung resistance in a time-dependent fashion that was not abolished by indomethacin or vagotomy. 3. Bronchoprotective effect of PAR2-AP was not reversed by the cyclo-oxygenase inhibitor, indomethacin, the nitric oxide synthetase inhibitor, L-NAME, nor by the non-selective beta-antagonist, propranolol. 4. Indomethacin augmented the bronchoconstriction to histamine which was inhibited by PAR2-AP. Furthermore, in vagotomized animals, the bronchial hyper-responsiveness to histamine was significantly reduced, and in these circumstances, PAR2-AP still retained the capacity to provide bronchoprotection against histamine. 5. PAR2-AP also produced a modest reduction in histamine-induced protein leakage in trachea and upper bronchi. 6. Our results indicated that PAR2 might have a bronchoprotective role in the guinea-pig in vivo independent of prostaglandin or nitric oxide release.

Analysis of Variance↗

PubMed2001

Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects.

In the present study, for the first time, PDE4 subtypes were identified and semi-quantified in both CD4 and CD8 lymphocytes from healthy and asthmatic individuals. CD4 and CD8 lymphocytes from healthy and mild asymptomatic asthmatic subjects (receiving beta-agonist therapy only) were isolated from peripheral venous blood using appropriate antibody coated paramagnetic beads. PDE4 subtypes and beta-actin were identified by digoxigenin (DIG)-labelling reverse transcriptase-polymerase chain reaction and semi-quantified by DIG-detection enzyme-linked immunosorbance assay. In CD4 and CD8 lymphocytes PDE4A, PDE4B and PDE4D were detected, with no significant differences observed between healthy and asthmatic groups. In CD8 lymphocytes, enzyme subtype expression was lower and showed more intersubject variability. In functional studies investigating the effects of various PDE inhibitors on PHA-induced proliferation of mononuclear cells from healthy and asthmatic subjects, CDP840 (0.03 - 10 microM), rolipram (0.1 - 10 microM) and theophylline (10 microM - 1 mM) inhibited PHA-induced proliferation of mononuclear cells from healthy and asthmatic subjects in a concentration-dependent manner, although no significant difference was observed between the groups investigated. In additional studies, total monocyte cyclic AMP PDE activity was investigated in cells isolated from asthmatic subjects both prior to and 24 h after allergen challenge. Total monocyte cyclic AMP PDE activity remained unaffected following challenge of asthmatic subjects with either house dust mite or cat dander and was inhibited in a concentration-dependent manner by rolipram (0.01 - 100 microM) both before and after allergen challenge.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors.

The etiopathogenesis of thoracic aortic aneurysms is currently an issue of debate. The present study investigated ultrastructural, morphometric, and immunohistochemical aspects of smooth muscle cells (SMCs) in chronic aneurysm of the thoracic aorta (aneurysm group), aortic dilatation associated with valvular disease (valvular group), and dissection of the thoracic aorta (dissection group). Fragments of the ascending aorta that had been taken from the patients during coronary bypass surgery were used as controls. No significant difference was observed in the density of SMCs between the 3 pathologic groups put together and the controls. Only separate analysis of SMC density in each of the pathologic groups showed that the valvular group samples had significantly smaller amounts of SMCs in the internal layer of the media than the dissection group samples and controls. Ultrastructural analysis, in situ end labeling, propidium iodide assay, and DNA laddering did not show apoptosis of SMCs in the samples investigated. Ultrastructure of SMCs characteristic of the synthetic phenotype, together with increased expression of osteopontin in the media of pathologic thoracic aortas indicated the transition of SMCs from the contractile to the synthetic phenotype. Immunohistochemical investigation showed that medial SMCs in the samples taken from aortas of all 3 pathologic groups expressed stronger immunoreactivity for matrix metalloproteinase 1, 2, and 9 and tissue inhibitor of metalloproteinase 1 and 2 than the controls. The present study shows that during the formation of aneurysms, dissection of the thoracic aorta, or aortic dilatation associated with valvular disease, loss of SMCs was not of great importance with respect to their transition from the contractile to the synthetic type in leading to increased production of matrix metalloproteinases.

Adult↗

PubMed2001

Cell proliferation, cell death, E-cadherin, metalloproteinase expression and angiogenesis in gastric cancer precursors and early cancer of the intestinal type.

The aim of this study was to analyse the morphological, kinetic and molecular characteristics of low-grade (LGD) and high-grade dysplasias (HDG) in comparison with intestinal metaplasia type III (IM III) and normal mucosa (NM) as well as with early gastric cancer of the intestinal type (EGC). Based on this it was verified whether these categories are distinct, progressive proliferative steps from IM III to LGD, HGD and EGC, according to Correa's sequence of events. The morphology, mitotic index (MI), and the apoptotic index (AI) were assessed. The E-cadherin expression (E-Cad), matrix-metalloproteinase activity (MMP2), and the number of microvessels (NV) were also evaluated. Among the categories, MI increases from NM to IM III and LGD, and from LGD to HGD and EGC, while AI continues to increase also from HGD to EGC. E-cad decreases from NM to EGC, although not significantly from LGD to HGD; MMP2 is significantly more expressed only in EGC. Three groups are obtained by means of cluster analysis. The first group includes all the NMs and IM IIIs, all except 1 LGD, about half of HGDs, and 1 EGC. E-Cad is highly expressed, MMP2 and angiogenesis are low, the proliferative activity is low and mitoses are partly balanced by apoptoses. The second group includes some EGCs and HGDs and is characterised by a very high proliferative activity and cell death; there is an initial loss of cell adhesion, an increase of MMP2 and NV. The third group includes the majority of EGCs, but also 1 HGD: it has intermediate MI and AI, the lowest expression of E-Cad, the highest expression of MMP2 and the most numerous microvessels. These results underscore the necessity of evaluating each case individually within the same singular category of Correa's sequence. The use of kinetic and molecular parameters in addition to the morphological analysis may give important information on the behaviour of the various lesions.

Cadherins↗

PubMed2000

What have transgenic and knockout animals taught us about respiratory disease?

Over the past decade there has been a significant shift to the use of murine models for investigations into the molecular basis of respiratory diseases, including asthma and chronic obstructive pulmonary disease. These models offer the exciting prospect of dissecting the complex interaction between cytokines, chemokines and growth related peptides in disease pathogenesis. Furthermore, the receptors and the intracellular signalling pathways that are subsequently activated are amenable for study because of the availability of monoclonal antibodies and techniques for targeted gene disruption and gene incorporation for individual mediators, receptors and proteins. However, it is clear that extrapolation from these models to the human condition is not straightforward, as reflected by some recent clinical disappointments. This is not necessarily a problem with the use of mice itself, but results from our continued ignorance of the disease process and how to improve the modelling of complex interactions between different inflammatory mediators that underlie clinical pathology. This review highlights some of the strengths and weaknesses of murine models of respiratory disease.

Animals↗

PubMed2000

A biochemical and functional assessment of monocyte phosphodiesterase activity in healthy and asthmatic subjects.

The aim of this study was to investigate whether cyclic adenosine 3'5-monophosphate (cAMP) phosphodiesterase (PDE) activity is altered in monocytes from mild asthmatic subjects. Total cAMP PDE activity (pmol/min per mg protein) was significantly greater in homogenates prepared from monocytes from asthmatic subjects (68.3 +/- 7.0, n=9) compared to healthy individuals (46.3 +/- 3.3, n=14, P<0.05). The PDE inhibitors siguazodan (PDE3-selective), rolipram (PDE4-selective) and theophylline (non-selective) produced a concentration-dependent inhibition of cAMP PDE activity in homogenates from monocytes from normal and asthmatic subjects. However, siguazodan produced significantly greater (P<0.05), and rolipram significantly less (P<0.05), inhibition of total cAMP PDE activity in monocytes from asthmatics (n=4) than from healthy individuals (n=5). cAMP PDE activity was inhibited with equal potency by theophylline in monocytes from healthy and asthmatic subjects. We also investigated the functional consequences of the changes in PDE activity in mononuclear cells obtained from asthmatic subjects. There was no significant difference in the ability of PDE4 inhibitors to attenuate TNF alpha release from monocytes obtained from asthmatic compared with healthy subjects (P>0.05). Despite a significant increase in the biochemical activity of PDE3 in monocytes from asthmatic subjects, the PDE3 inhibitor siguazodan, failed to significantly reduce TNF alpha release from human monocytes. Thus, total cAMP PDE activity is increased in monocytes taken from mild asymptomatic asthmatics compared to healthy subjects and is reflected by an increase in the proportion of PDE3 and a decrease in the proportion of PDE4. This augmented enzyme activity was not associated with an alteration in the ability of PDE4 inhibitors to attenuate mononuclear cell function from asthmatics compared to healthy individuals.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2000

Cytokines in airway inflammation.

With over 50 potential asthma mediators, cytokines are the latest group of substances which have been investigated for their potential role in this disease. The use of murine models of allergic inflammation has facilitated the investigation of the role of individual cytokines in this response. The use of targeted gene disruption, overexpression of genes and monoclonal antibodies directed against cytokines have allowed a detailed examination of the role cytokines play in IgE production, eosinophil recruitment and bronchial hyperresponsiveness, which are the characteristic features of the asthma phenotype. Despite the introduction of this new methodology, conflicting reports relating to the role of cytokines in allergic inflammation, highlight the complexity of allergic inflammation and challenge the notion that a single cytokine can explain the asthma phenotype.

Animals↗

PubMed2000

Murine models of inflammation: role of CD23.

The role of IgE in eosinophil recruitment and bronchial hyperresponsiveness has been extensively studied with murine models of inflammation. Many investigators using various knockout models have clearly shown that both IgE-dependent and -independent pathways play a role in eosinophil recruitment and bronchial hyperresponsiveness after allergen challenge, illustrating the complexity of airways inflammation. The expression of this response is likely to involve many interacting pathways, and it will be a considerable challenge to determine key points within these pathways that will yield novel targets for future therapeutic strategies.

Animals↗

PubMed2000

The role of adenosine receptors in the action of theophylline on human peripheral blood mononuclear cells from healthy and asthmatic subjects.

1. The aim of the present study was to investigate the role of adenosine A2b receptors in the anti-proliferative action of theophylline in human peripheral blood mononuclear cells (HPBMC) from healthy and asthmatic subjects. 2. Theophylline significantly inhibited PHA-induced proliferation of HPBMC from both healthy and asthmatic donors but only at relatively high concentrations at 1 mM (P<0.05). Enprophylline, a drug which also acts as a non-selective phosphodiesterase (PDE) inhibitor and is a selective A2b receptor antagonist, had no significant effect on proliferation of cells from either group at concentrations up to 10 microM (P>0.05; n=6). 3. Adenosine deaminase (2 u ml(-1)), which metabolizes adenosine, had no significant effect on PHA-induced HPBMC proliferation over a range of concentrations (0 - 8 microg ml(-1)) in cells from either healthy or asthmatic subjects. 4. The adenosine receptor agonists N(6)-cyclopentyladenosine (CPA, A1-selective) and 5'-N-ethylcarboxamidoadenosine (NECA, A1/A2) produced a small but significant inhibition of PHA-induced proliferation of HPBMC from healthy and asthmatic subjects (10 microM, P<0.05; n=6). In contrast, 5'-N-ethylcarboxamido-2-[4-(2-]carboxyethyl)phenethyl]adenosine (CGS21680, A2a-selective) was without significant effect (P>0.05; n=6). 5. The adenosine receptor antagonist alloxazine (A2b-selective) had no significant effect, while 8(3-chlorostyryl)caffeine,(CSC, A2a-selective) significantly inhibited PHA-induced proliferation of HPBMC from both groups (P<0.05; n=6). 6. Our results suggest that endogenous or exogenous adenosine has little effect on the proliferation of HPBMC obtained from healthy or asthmatic subjects. Thus it would appear that the effect of high concentrations of theophylline is not related to adenosine receptor antagonism.

Adenosine Deaminase↗

PubMed2000

The role of CD23 on allergen-induced IgE levels, pulmonary eosinophilia and bronchial hyperresponsiveness in mice.

BACKGROUND: The role of Immunoglobulin (Ig)E in inflammation is the subject of considerable study and a number of studies have shown conflicting evidence for its role in eosinophil recruitment and bronchial hyperresponsiveness in a number of murine models. The low affinity IgE receptor, CD23, is known to act as a negative regulator of IgE production and we have used knockout mice deficient in CD23 to investigate the role of IgE in eosinophil recruitment and bronchial hyperresponsiveness in a murine model of airway inflammation. OBJECTIVE: To study the role of the low affinity FcepsilonII receptor, CD23 in IgE production, lung inflammation and bronchial hyperresponsiveness. METHODS: Wild-type and CD23 knockout C57Bl/6 mice (CD23-/-) were immunized by intraperitoneal injection with ovalbumin on days 0 and 14 and challenged with aerosolized antigen on day 21 for a period of up to 1 week. Blood samples, bronchoalveolar lavage and lung tissue samples were obtained to determine serum IgE levels and inflammatory cell numbers, respectively. Furthermore, airway resistance was measured to increasing concentrations of aerosolized 5-hydroxytryptamine in order to evaluate the effect of CD23 deficiency on bronchial hyperresponsiveness to antigen challenge. RESULTS: Sensitization of wild-type C57Bl/6 mice to ovalbumin resulted in elevated levels of total serum IgE and ovalbumin-specific IgE, which was significantly augmented in CD23 knockout C57Bl/6 mice (CD23-/-). A significant increase in the percentage of eosinophils recovered in bronchoalveolar lavage fluid from wild-type and CD23-/- mice was observed 24 h following 3 or 7 days aerosol exposure with ovalbumin (10 mg/mL). At 3 days, the increase in the percentage of eosinophils was significantly greater in CD23-/- groups. Immunohistochemical analysis of lungs sections revealed the presence of CD3+, CD4+ and CD23+ cells in wild-type mice but a lack of immunofluorescence of CD23+ cells in CD23-/- mice. In wild-type ovalbumin-immunized mice, bronchial hyperresponsiveness to aerosolized 5-hydroxytryptamine was observed following a 3-day antigen challenge, which was significantly greater in CD23-/- ovalbumin-immunized mice. CONCLUSION: These studies demonstrate that CD23-/- mice have increased capacity to produce IgE consistent with the view of a negative feedback role for membrane-bound CD23 and under such conditions, may account for the greater numbers of eosinophils recruited to the airways and bronchial hyperresponsiveness observed following acute but not chronic antigen challenge.

Allergens↗