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ABSTRACT: Interleukin-1 receptor like 1 (ST2) is a negative regulator of Toll-like receptor (TLR) signaling. TLRs are important for host defense during respiratory tract infections by both influenza and Streptococcus (S.) pneumoniae. Enhanced susceptibility to pneumococcal pneumonia is an important complication following influenza virus infection. We here sought to determine the role of ST2 in primary influenza A infection and secondary pneumococcal pneumonia. ST2 knockout (st2 -/-) and wild-type (WT) mice were intranasally infected with influenza A virus; in some experiments mice were infected 2 weeks later with S. pneumoniae. Both mouse strains cleared the virus similarly during the first 14 days of influenza infection and had recovered their weights equally at day 14. Overall st2-/- mice tended to have a stronger pulmonary inflammatory response upon infection with influenza; especially 14 days after infection modest but statistically significant elevations were seen in lung IL-6, IL-1β, KC, IL-10, and IL-33 concentrations and myeloperoxidase levels, indicative of enhanced neutrophil activity. Interestingly, bacterial lung loads were higher in st2-/- mice during the later stages of secondary pneumococcal pneumonia, which was associated with relatively increased lung IFN-γ levels. ST2 deficiency did not impact on gross lung pathology in either influenza or secondary S. pneumoniae pneumonia. These data show that ST2 plays a limited anti-inflammatory role during both primary influenza and postinfluenza pneumococcal pneumonia.
PLoS ONE 01/2013; 8(3):e58191. · 4.09 Impact Factor
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ABSTRACT: BACKGROUND: Episodes of microvascular proliferation associated with volume expansion have been observed in arteriovenous malformations (AVMs) of skin and soft tissue. OBJECTIVE: We sought to investigate the relationship between a microvascular proliferative response and flow velocity in AVMs. METHODS: Resection specimens of 80 AVMs were clinically categorized as either high- or low-flow lesions, and histopathologically screened for the presence of microvessels, inflammation, thrombosis, or a combination of these. Immunohistochemistry was performed with endoglin (CD105), von Willebrand factor, and fibrinogen antibodies. RESULTS: Clinically, 37 AVMs were classified as high-flow lesions and 43 as low-flow lesions. In 81% of high-flow lesions microvascular proliferations were seen versus in 14% of low-flow lesions (P < .005). In high-flow lesions, which were embolized before surgery (30% of all), 88% showed microvascular proliferation, 88% inflammation, and 33% thrombosis. However, similar vasoproliferative responses were also observed in nonembolized AVM (69% high-flow and 14% low-flow lesions). Endoglin was more frequently expressed in high-flow lesions. Extracellular von Willebrand factor staining was found in most lesions, irrespective of flow type or presence of microvascular proliferations. LIMITATIONS: The study was carried out at a single tertiary referral center. CONCLUSIONS: Microvascular proliferative masses in AVMs appear to be strongly associated with high-flow characteristics. This could be explained to some extent by previous therapeutic embolization and/or inflammation in the lesion. However, occurrence of similar microvascular responses in AVM that were not embolized before surgery suggests that the biomechanical effects of high flow in these lesions may also have an angiogenic effect.
Journal of the American Academy of Dermatology 12/2012; · 3.99 Impact Factor
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J Daan de Boer,
Joris J T H Roelofs,
Alex F de Vos,
Regina de Beer,
Marcel Schouten,
Tijmen J Hommes,
Arie J Hoogendijk, Onno J de Boer,
Ingrid Stroo,
Jaring S van der Zee,
Cornelis van 't Veer,
Tom van der Poll
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ABSTRACT: Abstract The complex biology of asthma compels to use more relevant human allergens, such as house dust mite (HDM), to improve translation of animal models to human asthma. Lipopolysaccharide (LPS) exposure is associated with aggravation of asthma but mechanisms remain unclear. Here, we studied the effects of increasing LPS doses on HDM-evoked allergic lung inflammation. To this end mice were intranasally sensitized and challenged with HDM with or without increasing doses of LPS (0.001 - 10 µg). LPS dose-dependently inhibited HDM-induced eosinophil recruitment into the lungs and mucus production in the airways. LPS attenuated the production of Th2-cytokines (IL-4, IL-5, IL-10, IL-13) in HDM-challenged lungs, while enhancing HDM-induced release of IL-17, IL-33, IFN-γ and TNF-α. The shift towards a Th1 inflammatory response was further illustrated by a predominant neutrophilic lung inflammation after LPS administration at higher doses. LPS did not influence HDM-induced plasma IgE levels. While LPS did not significantly impact on activation of coagulation or complement in HDM-challenged lungs, it reduced HDM-initiated endothelial cell activation. This study is the first study to give insight in the effect of LPS in an allergic lung inflammation model making use of a clinically relevant allergen without systemic adjuvant, revealing that LPS dose-dependently inhibits HDM-induced pulmonary Th2 responses.
American Journal of Respiratory Cell and Molecular Biology 12/2012; · 5.13 Impact Factor
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ABSTRACT: BACKGROUND: Asplenic individuals are susceptible for overwhelming infection with Streptococcus pneumoniae, carrying a high mortality. Although Toll-like receptor (TLR)-2 is considered the major receptor for Gram-positive bacteria in innate immunity, it does not play a major role in host defense against pneumococcal pneumonia. We wanted to investigate if in absence of an intact spleen as a first line of defense, the role of TLR2 during pneumococcal pneumonia becomes more significant, thereby explaining its insignificant role during infections in immune competent hosts. METHODS: We intranasally infected splenectomized wildtype (WT), TLR2 knock-out (KO) and TLR2/4 double KO mice with either serotype 2 or 3 S. pneumoniae. RESULTS: There were no differences between asplenic WT and TLR2KO mice of bacterial loads in lung homogenates and blood, cytokine and chemokine levels in the lungs, and lung pathology scores. TLR2/4 double KO mice were not impaired in bacterial control as well, which indicates that besides the interaction between S. pneumoniae and TLR2, the interaction between pneumolysin and TLR4 does not stimulate antibacterial defense in the asplenic host either. CONCLUSIONS: These results argue against a significant role of TLR2 in host defense during S. pneumoniae pneumonia in the asplenic state. Therefore, other components can provide sufficient backup mechanisms for TLR2 deficiency in the defense against intrapulmonary infections with S. pneumoniae of the otherwise immune competent host.
BMC Infectious Diseases 06/2012; 12(1):139. · 3.12 Impact Factor
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ABSTRACT: Areas of microvascular proliferation have been observed in a subpopulation of symptomatic congenital vascular malformations later in life. We investigated whether this angiogenic response is followed by a stage of maturation.
Resections of vascular malformations (n = 15), infantile hemangiomas (IHs) (n = 8) and pyogenic granulomas (PGs) (n = 5) were studied. Histopathologically, all lesions were screened for presence of foci of immature and/or mature microvessels. These areas were further studied immunohistochemically for differential expression of several angiogenic factors, cell cycle-dependent proteins, p53 and active caspase3. Immunostains were scored semiquantitatively.
Immature microvessel areas were present in five vascular malformations (all of the arteriovenous type), five IHs and five PGs; these lesions also contained transitions between immature and mature microvessels. Conglomerates of mature microvessels were found in 19 cases (6 vascular malformations, 5 PGs and 8 IHs). Expression of vascular endothelial growth factor-A, angiopoietin-1, Ki-67, p16 and p21/27 ratios were overall significantly lower in mature areas than in immature areas including those in vascular malformations. P53 and caspase3 expression was scarce in all lesions.
Microvascular areas in vascular malformations appear to follow the same pattern of vascular proliferation and maturation as seen in other microvascular lesions of skin and soft tissue.
Journal of Cutaneous Pathology 06/2012; 39(6):610-20. · 1.56 Impact Factor
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ABSTRACT: Vulnerable atherosclerotic plaques are lesions with a high propensity to develop plaque disruption and superimposed thrombosis. No systematic studies have been carried out on tissue markers for plaque vulnerability throughout the entire coronary artery system at the end stages of coronary atherosclerosis.
Nine autopsied patients (mean age 77 years) with angiographically severe trivascular coronary atherosclerosis were selected for this study. All visible lesions in postmortem coronary angiograms (n = 125) were histologically and immunohistochemically screened for the presence of intraplaque haemorrhages (activated) microvessels and inflammatory infiltrates. Intraplaque haemorrhages were observed in 76/125 plaques (61%). Chronic inflammation was found superficially in 59/125 plaques (47%) and deeply inside the plaque tissue in 103/125 plaques (83%). Microvessels were found in 100/125 lesions (80%), of which 58% showed endothelial expression of the vascular activation marker CD105. Moreover, microvascular CD105 positivity correlated positively with plaque haemorrhage and deeply seated plaque inflammation.
Plaque inflammation and haemorrhages can be found at a high frequency throughout the coronary artery system of elderly patients with multivessel coronary atherosclerosis. Microvascular expression of endoglin (CD105), which correlates positively with both of these features of plaque vulnerability, can serve as a marker of the risk of developing coronary thrombotic complications.
Histopathology 03/2012; 61(1):88-97. · 3.08 Impact Factor
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XiaoFei Li,
Miranda C Kramer,
Chris M van der Loos,
Karel T Koch, Onno J de Boer,
José P S Henriques,
Jan Baan,
Marije M Vis,
Jan J Piek,
Jan G P Tijssen,
Robbert J de Winter,
Allard C van der Wal
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ABSTRACT: Inflammation plays a crucial role in plaque vulnerability. Calcifications can be detected by means of in vivo imaging techniques. The study purpose is to assess a potential association between tissue localization of calcifications and the inflammatory biomarkers, C-reactive protein (CRP), osteopontin and lipoprotein-associated phospholipase A2 (Lp-PLA2), in plaque tissue of patients with acute myocardial infarction (AMI).
Thrombectomy materials obtained from patients with electrocardiographically documented ST-segment elevation type of AMI (STEMI) were histologically screened for presence of thrombus, plaque tissues and calcifications. Size of calcifications was measured morphometrically, and their colocalization with the inflammatory biomarkers macrophages, CRP, osteopontin and Lp-PLA2 was assessed with immunostaining. A total of 171 samples containing plaque tissues were obtained from 562 thrombectomy procedures. Calcifications were observed in 67 (39%) plaque fragments, with diameters ranging from 4 to 170 μm. Plaque tissues with calcifications contained more frequently extracellular CRP and intracellular CRP in macrophages than those without calcifications (85%, 59% vs. 64%, 32%, P=0.012 and 0.005 respectively). Similar results were obtained with osteopontin immunostaining (98%, 76% vs. 56%, 40%; P<0.001 both). Furthermore, samples with calcifications were immunostained for CRP more intensely than those without calcifications (P=0.001). Finally, 96% of the plaque tissues stained positively for Lp-PLA2, but there was no association with presence of microcalcifications.
A pattern of disperse microcalcifications is positively associated with presence of the inflammatory biomarkers macrophages, CRP and osteopontin in thrombectomy materials of STEMI patients. Based on these findings, we speculate that such microcalcifications could have the potential to serve as a surrogate marker for plaques with high inflammatory burden.
Atherosclerosis 05/2011; 218(1):83-9. · 3.79 Impact Factor
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ABSTRACT: Interleukin (IL)-15 is a cytokine that has a broad tissue distribution and is important in maintaining homeostasis of cells and stability of tissues. When II-15 is also expressed by vascular smooth muscle cells (SMC), which are the dominant type of cells in most atherosclerotic plaques, it could be important in maintaining plaque tissue integrity and hence resistance of plaques towards development of clinically relevant complications such as plaque rupture and thrombosis. In this study, IL-15 and IL-15Rα in vitro expression by coronary artery SMC was investigated using RT -PCR and FACS analysis. Immunohistochemistry was used to study in situ expression of IL-15 and IL-15R by SMC of human carotid artery atherosclerotic plaques. Multiplex ligand-dependent probe amplification (MLPA) was used to investigate the mRNA expression of 40 pro- and anti inflammatory genes after stimulating coronary SMC with IL-15. We found that atherosclerotic SMC express both IL-15 and its receptor IL-15R, and TNF-γ and TNF-α enhance IL-15R expression in cultured SMC. MLPA studies on SMC revealed enhanced expression of PDGF beta mRNA after IL15 stimulation. In conclusion, our data suggest that IL-15 may contribute to atherosclerotic plaque integrity by stimulation of smooth muscle cells, probably in a PDGF dependent fashion.
International journal of clinical and experimental pathology 03/2011; 4(3):287-94. · 1.89 Impact Factor
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ABSTRACT: Patients without a spleen are susceptible for overwhelming sepsis with Streptococcus pneumoniae. We investigated the relative contribution of the pneumococcal capsule in the reduced host defense after splenectomy. Sham-operated or splenectomized mice were inoculated with serotype 2 or 4 S. pneumoniae (D39, TIGR4) or the isogenic nonencapsulated mutants (D39Δcps, TIGR4Δcps). After splenectomy, intranasal infection with D39 resulted in increased mortality, increased bacterial dissemination and exaggerated systemic inflammation rather then altering inflammation in the lungs. Intravenous infection also resulted in enhanced mortality, bacterial growth and systemic inflammation after splenectomy. In contrast, the spleen did not contribute to host defense during infection with D39Δcps. Similar observations were made for TIGR4: increased bacterial growth and inflammation after intravenous infection with wild-type, but not nonencapsulated bacteria in splenectomized mice. These results indicate that the capsule of S. pneumoniae is indeed responsible for increased vulnerability of asplenic mice to invasive pneumococcal disease.
Immunobiology 02/2011; 216(8):863-70. · 3.20 Impact Factor
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ABSTRACT: Allograft vasculopathy (AV) and native atherosclerosis (NA) share the presence of a T-cell mediated inflammatory response, but differ in overall plaque morphology and growth rate. We studied the distribution and frequency of regulatory- and cytotoxic T cells in the arterial intima lesions in both conditions.
The study is based on vessels of 15 explanted human renal allografts with AV and 10 carotid artery plaques obtained at surgery. Distribution and frequency of cytotoxic- and regulatory T cells, as identified by the expression of Granzyme B (GrB) and FOXP3 was established in NA and AV. Furthermore, we compared the distribution of these cells in AV with the perivascular, interstitial renal tissue using immunohistochemistry. The total number of T cells was much higher in AV than in NA lesions (711±135 and 37±8 CD3/mm(2) respectively, p<0.005, mean, ± SEM). Total numbers of FOXP3(+) regulatory cells were also significantly increased in AV (36±10 and 0.9±0.3 FOXP3(+)/mm(2) p<0.05), but relative numbers, expressed as a percentage of the total number of CD3(+) T cells ((FOXP3(+)/CD3(+)) ×100), were not significantly different (4.6%±0.9 and 2.7%±0.6). GrB(+) cells were rare in NA, but significantly increased numbers of GrB(+) cells were found in AV lesions (85±24 and 0.2±0.1 GrB(+)/mm(2), p<0.05). Perivascular tissues in the allografts showed a higher relative frequency of FOXP3(+) cells than adjacent intimal lesions (14.0%±2.7 and 4.6%±0.9, respectively, p<0.05), but a lower frequency of GrB(+) cytotoxic T cells (16.1%±2.7 and 22.6%±3.6, p<0.05).
Similar to NA, AV is characterized by a low frequency of intimal FOXP3(+) regulatory T cells. Moreover, significant spatial differences exist in the distribution of functional T cell subsets between the intra- and extravascular micro-environments of the graft.
PLoS ONE 01/2011; 6(4):e18656. · 4.09 Impact Factor
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Christian Anderwald,
Hendrik J Ankersmit,
Abdenor Badaoui,
Luca Beneduce,
Vyacheslav U Buko,
Lorenzo A. Calo,
Juan J Carrero,
Chun-Yi Chang,
Kuo-Chu Chang,
Yi-Jen Chen, [......],
Peter Stenvinkel,
Peter Strasser,
Hiroshi Suzuki,
Alexander Tschoner,
Allard C van der Wal,
David L Vesely,
Chiung-Jung Wen,
Ireneusz Wiernicki,
Giuliana Zanninelli,
Y Zhu
European Journal of Clinical Investigation 09/2010; 40(9):770-789. · 3.02 Impact Factor
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Sander I van Leuven,
Diederik F van Wijk,
Oscar L Volger,
Jean-Paul P M de Vries,
Chris M van der Loos,
Dominique V P de Kleijn,
Anton J G Horrevoets,
Paul P Tak,
Allard C van der Wal, Onno J de Boer,
Gerard Pasterkamp,
Michael R Hayden,
John J P Kastelein,
Erik S Stroes
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ABSTRACT: Atherosclerosis as well as the subsequent progression towards cardiovascular events are considered to, at least partially, be a consequence of chronic inflammatory activity. Therefore, we decided to evaluate the impact of short-term immunosuppressive treatment on plaque characteristics in patients with symptomatic carotid artery stenosis. Twenty-one patients were randomized to receive either 1000 mg. Mycophenolate mofetil (MMF) BD or placebo for at least 2 weeks prior to undergoing carotid endarterectomy (CEA). The serial sections of the CEA specimens were immunostained for activated T-cells (CD3+CD69+), regulatory T-cells (CD3+FOXP3+) and macrophages (CD68). In addition, gene expression profiling was performed by Illumina gene-array. Immunostaining revealed a reduction of activated T-cells in nine MMF-treated patients compared to 11 placebo-treated control patients (19.7% vs. 28.1%; p<0.05) as well as an increase of regulatory T-cells (3.8% vs. 1.8%; p=0.05). Microarray analyses confirmed beneficial changes to plaque phenotype, showing reduced expression of pro-inflammatory genes. Significantly reduced expression of metalloproteinases and osteopontin was observed in three out of nine MMF-treated patients compared to nil out of 11 in the placebo group. In the present study we show that immunosuppressive treatment for two-and-a-half weeks prior to CEA elicits changes in the plaque phenotype of symptomatic patients. These changes include reduced inflammatory cell presence with a concomitant decrease in pro-inflammatory gene expression.
Atherosclerosis 02/2010; 211(1):231-6. · 3.79 Impact Factor
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ABSTRACT: Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ.
By spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-γ (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well.
The increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17A(pos) CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cells.
PLoS ONE 01/2010; 5(11):e14108. · 4.09 Impact Factor
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ABSTRACT: In addition to the classical TH1 and TH2 cytokines, members of the recently identified IL-17 cytokine family play an important role in regulating cellular and humoral immune responses. At present nothing is known about the role of these cytokines in atherosclerosis. Expression of IL-17A, -E and -F was investigated in atherosclerotic tissue by rtPCR and immunohistochemistry. IL-17E and its receptor were further studied in cultured smooth muscle cells and endothelial cells, using rtPCR and western blot. rtPCR showed that IL-17A, -E and -F were expressed in the majority of plaques under investigation. IL-17A/F was expressed by mast cells in all stages of plaque development. IL-17A/F(+) neutrophils were always observed in complicated plaques, but hardly in intact lesions. IL-17A/F(+) Tcells ('TH17') were never observed. IL-17E was expressed by smooth muscle cells and endothelial cells in both normal and atherosclerotic arteries, and in advanced plaques also extensively by mature B cells. Cultured smooth muscle cells and endothelial cells were found to express both IL-17E and its functional receptor (IL-17RB). The constitutive expression of IL-17E by resident plaque cells, and the additional presence of IL-17E(+) B cells and IL-17A/F(+) neutrophils in advanced and complicated plaques indicates a complex contribution of IL-17 family cytokines in human atherosclerosis, depending on the stage and activity of the disease.
The Journal of Pathology 11/2009; 220(4):499-508. · 6.32 Impact Factor
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ABSTRACT: Recently, Patel et al. reported that FOXP3 positive T cells are abundantly present in unstable atherosclerotic plaques. However, there is also evidence from immunohistochemical studies in humans, as well as experimental animal studies that their numbers are in fact relatively low. Since Treg are able to dampen tissue immune responses, their low numbers in plaques could be responsible for the ongoing inflammation that characterizes atherosclerosis.
International journal of cardiology 09/2009; 145(1):161. · 7.08 Impact Factor
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ABSTRACT: Nine commercially available vascular endothelial growth factor (VEGF) antibodies were investigated for their ability to immunostain vascular malformations (VMs) with or without immature capillary proliferation. First, all antibodies were optimized for their performance in IHC, with placenta and colon adenocarcinoma as positive control tissues. Five antibodies were regarded as unfit for VEGF immunostaining based on poor immunostaining criteria. Subsequently, Western blot analysis using VEGF rabbit polyclonal antibody (Thermo RB-9031) revealed a clear 45-kDa band in tissue extracts from VMs with immature capillary proliferation and a high Ki67-labeling index, whereas tissue extracts from mature VMs without microvascular proliferation and no Ki67-labeling index demonstrated only a very weak 45-kDa band. In contrast, two VEGF antibodies, including the popular Santa Cruz A-20, revealed bands at 45 kDa of similar intensity in tissue extracts from both types of VMs. Staining characteristics of the 45-kDa band were reflected in the results obtained in IHC. (J Histochem Cytochem 58:109-118, 2010).
Journal of Histochemistry and Cytochemistry 09/2009; 58(2):109-18. · 2.72 Impact Factor
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ABSTRACT: We compared in vivo 3.0-T magnetic resonance (MR) images of the carotid artery wall in piglets to intima-media thickness measurements of similar carotid segments by B-mode ultrasound (US) and histology to define the corresponding anatomical tissue characteristics and accuracy of carotid MR images.
Carotid MR is increasingly used for the assessment of cardiovascular risk and cardiovascular drug efficacy. Therefore, determining the anatomical correlate and accuracy of this modality is of major importance.
In vivo 3.0-T MR and B-mode US scans of the left and right common carotid arteries were performed in 5 piglets (75 to 80 kg). The T(1)-weighted MR images were acquired with a noninterpolated pixel size of 0.25 x 0.25 mm for mean wall area (MWA) and mean wall thickness measurements. The B-mode US measured common carotid intima-media thickness and common carotid diameter. We calculated US MWA using common carotid intima-media thickness and carotid diameter. In histology, the intima and media tissue area was defined as histology MWA.
Histology MWA was 4.69 (standard deviation [SD]: 0.95) mm(2), MR MWA was 4.57 (SD: 0.41) mm(2), and US MWA was 4.90 (SD: 0.50) mm(2). The mean difference was 0.12 (SD: 1.11) mm(2) for MR and -0.21 (SD: 1.01) mm(2) for US when compared with histology. Bland-Altman analysis showed no systematic biases between MR, US, or histology.
Absolute values for carotid artery histology, MR, and US measurements are in good agreement, indicating that both 3.0-T MR and B-mode US measurements can visualize the intima and media. Accuracy of 3.0-T MR is comparable to B-mode US. The present findings imply that carotid MR might be a novel asset in cardiovascular disease risk stratification and a valuable surrogate marker in cardiovascular prevention trials.
JACC. Cardiovascular imaging 07/2009; 2(6):744-50. · 14.29 Impact Factor
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ABSTRACT: Congruency of the development of peripheral nerves and blood vessels has been well described, and usually, the nerves and blood vessels follow each other during development. Although little is known about the existence of a substantial neural component in vascular malformations, we investigate the presence of an intralesional component of nerve bundles in congenital vascular malformations of soft tissues. Resection specimens of 130 congenital vascular malformations of soft tissue were retrospectively screened for the presence and extent of intralesional mature nerves bundles. Lesions were histologically categorized in arteriovenous malformations (n = 83), pure venous malformations (n = 33), and lymphatic-venous malformations (n = 14). For identification of nerves, all sections were immunostained with anti-S100. GLUT-1 immunostaining excluded the presence of infantile hemangiomas in these series. Of 130 cases, 96 (74%) showed a substantial increase of intralesional nerves in close apposition to the vessels. The nervous component appeared to be more extensive in the head and neck region and upper extremities than in malformations of other topographic sites. Most cases of arteriovenous malformations showed an increase in nerve elements (87% of all arteriovenous malformations), which was more than in pure venous malformations (55%). In cases of lymphatic-venous malformations, the areas composed of lymphatic vessels showed an almost complete absence of nerves. Prior surgery in the malformation gave no different nerve pattern compared to cases that were surgically treated for the first time. The abundant presence of intralesional mature nerves in most congenital vascular malformations suggests that at least in a large subset of lesions, neural components are an integral part of the developmental disorder. This is particularly evident in the arteriovenous type of malformations and lesions that arise in the head and neck region of the body.
Human pathology 06/2009; 40(10):1467-73. · 3.03 Impact Factor
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ABSTRACT: Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR-/-) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR-/- neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR-/- mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.
The Journal of Immunology 04/2008; 180(5):3357-65. · 5.79 Impact Factor
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ABSTRACT: Evidence is accumulating that infection with influenza A virus contributes to atherothrombotic disease. Vaccination against influenza decreases the risk of atherosclerotic syndromes, indicating that inflammatory mechanisms may be involved. We tested the hypothesis that influenza A virus-specific T cells contribute to atherosclerotic plaque inflammation, which mediates the onset of plaque rupture.
T-cell cultures were generated from atherosclerotic segments and peripheral blood of 30 patients with symptomatic carotid artery disease. The response of plaque and peripheral blood T cells to influenza A virus was analyzed and expressed as a stimulation index (SI). Selective outgrowth of intraplaque influenza A-specific T cells was calculated by the ratio of plaque T cell SI and peripheral blood T cell SI for each patient. Accordingly, the patients were categorized as high- (SI ratio >or=5), intermediate- (5 <SI ratio <or=2), and non- (SI ratio <2) responders. The presence of influenza A virus in the vessel fragments was evaluated by reverse transcription-polymerase chain reaction.
High proliferative responses of plaque-derived T cells to influenza A virus were frequently observed. Among the 30 patients, 5 were categorized as high responders, 10 were intermediate responders, and 15 were nonresponders. Live influenza A virus could not be detected in the atherosclerotic plaques by polymerase chain reaction.
Selective outgrowth of influenza A virus-specific T cells occurs within the microenvironment of human atherosclerotic plaques. Influenza virus-derived antigens or alternatively, mimicry antigens, appear to be potential candidates for triggering or sustaining plaque inflammation, which eventually leads to symptomatic plaque complications.
Stroke 02/2008; 39(1):174-9. · 5.73 Impact Factor
