Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization.

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.

The role of interleukin-4Ralpha in the induction of glutamic acid decarboxylase in airway epithelium following acute house dust mite exposure.

Background Asthma is a disease characterized by airway inflammation, remodelling and dysfunction. Airway inflammation contributes to remodelling, a term that is used to describe structural changes including goblet cell metaplasia (GCM), matrix deposition, and smooth muscle hyperplasia/hypertrophy. GCM has been implicated in asthma mortality by contributing to mucus plugs and leading to asphyxiation. In animal models, this process is highly dependent on IL-13. Recently, we have described an IL-13-dependent up-regulation of a GABAergic signalling system in airway epithelium that contributes to GCM. The mechanism by which IL-13 up-regulates GABA signalling in airway epithelium is unknown. Objectives To test the hypothesis that IL-4Ralpha signalling is required for allergen induced up-regulation of GABAergic signalling and GCM. Methods BALB/c mice were exposed to an acute house dust mite (HDM) protocol and received vehicle, anti-IL-4Ralpha-monoclonal antibody, or control antibody. Outcomes included airway responses to inhaled methacholine (MCh), histology for eosinophilia and GCM, phosphorylated STAT6 levels using immunohistochemistry and immunoblot, and glutamic acid decarboxylase (GAD) 65/67 and GABA(A)beta(2/3) receptor subunit expression using confocal microscopy. Results Acute HDM exposure resulted in increased airway responses to MCh, lung eosinophilia, STAT6 phosphorylation, elevations in GAD65/67 and GABA(A)beta(2/3) receptor expression, and GCM that were inhibited with anti-IL-4Ralpha-monoclonal treatment. Control antibody had no effect. Conclusion The IL-4Ralpha is required for allergen-induced up-regulation of a GABAergic system in airway epithelium implicated in GCM following acute HDM exposure.

Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study.

BACKGROUND: Asthma is a disease characterized by variable and reversible airway obstruction and is associated with airway inflammation, airway remodelling (including goblet cell hyperplasia, increased collagen deposition and increased smooth muscle mass) and increased airway responsiveness. It is believed that airway inflammation plays a critical role in the development of airway remodelling, with IL-13 and TGF-beta1 pathways being strongly associated with the disease progression. Mouse models of asthma are capable of recapitulating some components of asthma and have been used to look at both IL-13 and TGF-beta1 pathways, which use STAT6 and SMAD2 signalling molecules, respectively. OBJECTIVES: Using brief and chronic models of allergen exposure, we utilized BALB/c and C57Bl/6 to explore the hypothesis that observed differences in responses to allergen between these mouse strains will involve fundamental differences in IL-13 and TGF-beta1 responses. METHODS: The following outcome measurements were performed: airway physiology, bronchoalveolar lavage cell counts/cytokine analysis, histology, immunoblots and gene expression assays. RESULTS: We demonstrate in BALB/c mice an IL-13-dependent phosphorylation of STAT6, nuclear localized in inflammatory cells, which is associated with indices of airway remodelling and development of airway dysfunction. In BALB/c mice, phosphorylation of SMAD2 is delayed relative to STAT6 activation and also involves an IL-13-dependent mechanism. In contrast, despite an allergen-induced increase in IL-4, IL-13 and eosinophils, C57Bl/6 demonstrates a reduced and distinct pattern of phosphorylated STAT6, no SMAD2 phosphorylation changes and fail to develop indices of remodelling or changes in airway function. CONCLUSION: The activation of signalling pathways and nuclear translocation of signalling molecules downstream of IL-13 and TGF-beta1 further support the central role of these molecules in the pathology and dysfunction in animal models of asthma. Activation of signalling pathways downstream from IL-13 and TGF-beta1 may be more relevant in disease progression than elevations in airway inflammation alone.

Effects of allergen on airway narrowing dynamics as assessed by lung-slice technique.

Asthma is characterised by an excessive airway narrowing in response to a variety of stimuli, called airway hyperresponsiveness (AHR). Previous comparisons between mouse strains have shown that increased velocity of airway narrowing correlates with baseline airway responsiveness. These data prompted the investigation into models of induced AHR to see whether airway narrowing dynamics correlated with in vivo responsiveness. In an attempt to reproduce some of the features of asthma, BALB/c mice were sensitised and subjected to either brief or chronic periods of allergen exposure. Brief exposure involved two challenges with intranasal chicken egg ovalbumin (OVA(in)). Chronic exposure involved six 2-day periods of OVA(in) challenges, each separated by 12 days. Control mice received intranasal saline challenges. Outcomes included videomicrometry of lung slices (magnitude and velocity of airway narrowing), in vivo respiratory physiology measurements and histological staining with morphometric analysis. Neither brief nor chronic allergen exposure resulted in greater airway narrowing and increased velocity compared with saline controls. Structural changes in the airway, such as goblet cell hyperplasia, subepithelial fibrosis and increased contractile tissue, were detected in mice chronically challenged with allergen. In conclusion, increased responsiveness to methacholine following allergen challenge may not be due to an intrinsic change to the smooth muscle per se, but rather to other changes in the lung, which ultimately manifest as an increase in respiratory resistance.

[Scimitar syndrome; report of a case].

A 17-year-old woman with scimitar syndrome without an atrial septal defect was operated by intra-cardiac conduit repair. Computed tomography (CT) and magnetic resonance imaging (MRI) showed resolution images of anatomical findings of scimitar vein. Surgical procedures for the scimitar syndrome have varied according to the anatomic features presented in each case. The detection of precise anatomy of scimitar syndrome is important for determining the appropriate surgical procedure. Images of 3-dimensional (3-D) CT and MRI of scimitar syndrome were demonstrated.

Newly developed left main coronary artery lesion after coronary stenting.

Percutaneous transluminal coronary stenting is a proven nonoperative method of direct myocardial revascularization. We encountered a case of iatrogenic significant subacute left main coronary artery stenosis in a patient who had undergone prior percutaneous transluminal coronary artery stenting of the left anterior descending (LAD) artery. Coronary artery bypass grafting was performed. To our knowledge, this is the first report of a surgical case of left main coronary artery stenosis worsened by changes secondary to earlier coronary stenting in the mid portion of left descending coronary artery in Japan.

Recurrent aortic valve endocarditis caused by Gemella morbillorum--report of a case and review of the literature.

Gemella morbillorum (G. morbillorum) is part of the commensal flora of the oropharynx and intestinal tract, and on rare occasions causes infective endocarditis. A 55-year-old man with massive aortic regurgitation caused by recurrent infective endocarditis with G. morbillorum had a history of prior endocarditis caused by alpha-hemolytic streptococcus and multiple antibiotic allergies 5 years prior, and was successfully treated by aortic valve replacement. Almost all the reported cases of endocarditis caused by G. morbillorum have been bacteriologically cured with antibiotics and this is the first reported case of recurrent endocarditis caused by G. morbillorum in which the initial infection was bacteriologically cured by antibiotics and the secondary infection treated with valve replacement. This organism can be one of the causes of infective endocarditis and prompt surgical repair is mandatory if the infection is refractory or there is progression of congestive heart failure under antibiotic cover.

[A case of protruding atherosclerotic plaque with mobile projections in the sino-tubular junction].

A 66-year-old woman who received maintenance hemodialysis for the last 14 years was referred to our hospital due to the sudden onset of ischemic stroke and systemic emboli. Transthoracic echocardiography before surgery showed large protruding masses measuring 2 cm which projected into the lumen of the aortic root. The plaque originated on a wide base of the posterior aspect of the ascending aorta at its junction with the sinus of Valsalva. The mobile plaque was surgically removed by endarterectomy from the posterior wall of sino-tubular junction under cardiopulmonary bypass. Pathologic examination of the masses removed at the time of surgery showed that they were atherosclerotic plaque with superimposed thrombi. During operation, transesophageal echocardiography appears to be useful for the rapid detection of a protruding aortic atheroma especially in the initial period of cardiopulmonary bypass until aortic cross clamp.

[Surgical treatment for aortic aneurysms associated with coronary artery disease-selection of bypass conduit].

Graft replacement for arch aneurysms and concomitant coronary artery bypass grafting (CABG) were performed in four consecutive patients over a three-year period between March 1995 and October 1998. The etiology of the aneurysms was atherosclerosis in all the patients. One early death as a result of a cerebellar infarction occurred on the 74th postoperative day. In all cases, respiratory failure frequently occurred after surgery. In a recent case, the internal mammary artery was used as a graft conduit to the left anterior descending artery (LAD). Both artery and vein grafts were anastomosed to coronary arteries during the initial core cooling. Selective cerebral perfusion was carried out during the reconstruction of the transverse aortic arch and its branches. The left subclavian artery was anastomosed first to secure perfusion to the LAD. To achieve sufficient myocardial protection and obtain good postoperative hemodynamics, CABG was simultaneously performed at the time of aortic aneurysm repair in cases complicated with coronary artery disease.

[Surgical treatment for chronic pulmonary thromboembolism in a patient with protein C deficiency].

Medical therapy for chronic pulmonary thromboembolism is limited, and surgical treatment has become more frequent recently. We have performed pulmonary thromboendarterectomy on a patient with chronic pulmonary thromboembolism accompanied by protein C deficiency. The patient was a woman aged 68 years who had protein C deficiency. The preoperative condition was New York Heart Association functional class IV. Hypoxemia, marked pulmonary hypertension, and low cardiac output were observed. After a median sternotomy, moderate hypothermia was induced using a cardiopulmonary bypass, and thromboendarterectomy in the pulmonary artery was performed. The arterial blood oxygen concentration improved, and the mean pulmonary pressure decreased. The cardiac output also increased, and New York Heart Association functional class improved to I. Pulmonary thromboendarterectomy under cardiopulmonary bypass was effective for chronic pulmonary thromboembolism accompanied by protein C deficiency.

Papillary fibroelastoma in association with thrombosis on a mechanical valve.

A patient with a thrombosed mechanical valve underwent valve re-replacement during which a tumor of the left ventricular outflow tract with the typical macroscopic and microscopic characteristics of a papillary fibroelastoma was successfully removed surgically. The 60-year-old woman had undergone isolated mitral valve replacement with a St Jude Medical 29-mm valve for mitral regurgitation 15 years ago. The present admission was for investigation of dyspnea on exertion. Two-dimensional transthoracic echocardiography demonstrated a posteroseptal, pedunculated mass, measuring 1.3x1.0 cm, in the outflow tract of the left ventricle, mild mitral regurgitation and slight aortic stenosis.

Sudden deterioration of aortic regurgitation due to rupture of a raphal cord on the conjoined cusp.

A 57-year-old man was admitted to hospital for acute myocardial infarction associated with mild aortic regurgitation, which was successfully treated by intracoronary thrombolysis. Twenty-four days later, he suffered from another chest pain attack without any electrocardiographic ST-T changes. The coronary angiogram did not show any significant lesions, but the aortic root angiogram showed massive aortic regurgitation. Surgery revealed a bicuspid aortic valve with a conjoined cusp that had a fenestrated raphe torn away from the aortic wall and prolapsing into the left ventricle. The aortic valve was successfully replaced with a St Jude Medical mechanical valve prosthesis. The pathological significance of the intact raphal cord and the rupture remains an unsolved problem. This is the first reported case in which an increase of aortic regurgitation due to a ruptured raphal cord supporting the conjoined cusp was confirmed by a serial root angiogram.

Unusual complications in an inflammatory abdominal aortic aneurysm.

An unusual case of an inflammatory abdominal aortic aneurysm (IAAA) associated with coronary aneurysms and pathological fracture of the adjacent lumbar vertebrae. The associated coronary lesions in cases of IAAA are usually occlusions. In the present case, it was concluded that a possible cause of the coronary aneurysm was coronary arteritis and the etiology of the pathological fracture of the lumbar vertebrae was occlusion of the lumbar penetrating arteries due to vasculitis resulting in aseptic necrosis. Inflammatory AAA can be associated with aneurysms in addition to occlusive disease in systemic arteries. The preoperative evaluation of systemic arterial lesions and the function of systemic organs is essential.

Inositol 1,4,5-trisphosphate receptor type 1 is a substrate for caspase-3 and is cleaved during apoptosis in a caspase-3-dependent manner.

The inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R), an IP(3)-gated Ca(2+) channel located on intracellular Ca(2+) stores, modulates intracellular Ca(2+) signaling. During apoptosis of the human T-cell line, Jurkat cells, as induced by staurosporine or Fas ligation, IP(3)R type 1 (IP(3)R1) was found to be cleaved. IP(3)R1 degradation during apoptosis was inhibited by pretreatment of Jurkat cells with the caspase-3 (-like protease) inhibitor, Ac-DEVD-CHO, and the caspases inhibitor, z-VAD-CH(2)DCB but not by the caspase-1 (-like protease) inhibitor, Ac-YVAD-CHO, suggesting that IP(3)R1 was cleaved by a caspase-3 (-like) protease. The recombinant caspase-3 cleaved IP(3)R1 in vitro to produce a fragmentation pattern consistent with that seen in Jurkat cells undergoing apoptosis. N-terminal amino acid sequencing revealed that the major cleavage site is (1888)DEVD*(1892)R (mouse IP(3)R1), which involves consensus sequence for caspase-3 cleavage (DEVD). To determine whether IP(3)R1 is cleaved by caspase-3 or is proteolyzed in its absence by other caspases, we examined the cleavage of IP(3)R1 during apoptosis in the MCF-7 breast carcinoma cell line, which has genetically lost caspase-3. Tumor necrosis factor-alpha- or staurosporine-induced apoptosis in caspase-3-deficient MCF-7 cells failed to demonstrate cleavage of IP(3)R1. In contrast, MCF-7/Casp-3 cells stably expressing caspase-3 showed IP(3)R1 degradation upon apoptotic stimuli. Therefore IP(3)R1 is a newly identified caspase-3 substrate, and caspase-3 is essential for the cleavage of IP(3)R1 during apoptosis. This cleavage resulted in a decrease in the channel activity as IP(3)R1 was digested, indicating that caspase-3 inactivates IP(3)R1 channel functions.

Calmodulin mediates calcium-dependent inactivation of the cerebellar type 1 inositol 1,4,5-trisphosphate receptor.

The dependency of purified mouse cerebellar type 1 inositol 1,4,5-trisphosphate receptor (IP3R1)/Ca2+ channel function on cytoplasmic Ca2+ was examined. In contrast to the channels in crude systems, the purified IP3R1 reconstituted into planar lipid bilayers did not show the bell-shaped dependence on Ca2+. It was activated with increasing Ca2+ sublinearly without inhibition even up to 200 microM. The addition of calmodulin to the cytoplasmic side inhibited the channel at high Ca2+ concentrations. Calmodulin antagonists reversed the Ca2+-dependent inactivation of the native channels in cerebellar microsomes. These results indicate that the bell-shaped dependence on cytoplasmic Ca2+ is not an intrinsic property of the IP3R1, and the Ca2+-dependent inactivation is directly mediated by calmodulin.