Nao Inoue

Role of Chymase-Dependent Matrix Metalloproteinase-9 Activation in Mice with Dextran Sodium Sulfate-Induced Colitis

Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of colitis. Recent studies have demonstrated that chymase is involved in the conversion of promatrix metalloproteinase (proMMP)-9 to MMP-9. However, whether chymase contributes to the activation of proMMP-9 in colitis has remained unclear. In this study, we administered 5% dextran sodium sulfate (DSS) solution to mice for 7 days. At 7 days after starting administration, both chymase activity and MMP-9 activity were significantly increased. In extract from colitis in DSS-treated mice, MMP-9 activity was significantly increased after 8 h of incubation, but increased activity was almost completely suppressed in the presence of a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide (NK3201). At 7 days after starting administration, intestinal length was significantly shorter in DSS-treated mice than in normal mice, but these changes were significantly prevented by NK3201 (10 mg/kg per day i.p.). Disease activity index and histological damage score were also significantly reduced by NK3201. The filtrated neutrophil number was significantly decreased by NK3201. Furthermore, NK3201 significantly attenuated not only chymase activity but also MMP-9 activity in DSS-treated mice. These findings suggest that chymase plays an important role in the development of colitis via MMP-9 activation.

Effects of chymase inhibitor on angiotensin II-induced abdominal aortic aneurysm development in apolipoprotein E-deficient mice

OBJECTIVE Chymase may play an important role in abdominal aortic aneurysm (AAA) development through matrix metalloproteinase (MMP)-9 activation. The purpose of this study was to determine whether chymase is involved in angiotensin (Ang) II-induced AAA development in apolipoprotein E (apoE)-deficient mice. METHODS AND RESULTS In this study, Ang II (1000 ng/kg/min; vehicle group) or saline (saline group) was administered to 16-week-old, male, apoE-deficient mice for 4 weeks. To examine the effects of chymase inhibition on AAA development, oral NK3201 (30 mg/kg/day) was given for the same period as the Ang II infusion. AAAs developed at the suprarenal region of the abdominal aorta in the Ang II-treated vehicle group, but they were not observed in the saline group. On the other hand, the severity and luminal area of the AAAs in the Ang II-treated vehicle group were significantly suppressed by NK3201 treatment. MMP-9 activity was significantly lower in the Ang II-treated+NK3201-treated group than in the Ang II-treated vehicle group. Furthermore, there were significantly fewer monocyte/macrophage cells in the Ang II-treated+NK3201-treated group than in the Ang II-treated vehicle group. CONCLUSIONS Chymase is involved in Ang II-induced AAA development in apoE-deficient mice.

Febrile seizures associated with influenza A

To clarify the clinical impact of influenza A on the development of febrile seizures (FS), consecutive FS patients brought to our hospital between October 2003 and September 2004 were prospectively surveyed. Patients infected with influenza A (influenza A patients) and those uninfected with influenza (non-influenza patients) were compared with regard to clinical characteristics of FS. Influenza infection was determined by rapid antigen test and/or serologically. Associations of influenza A with atypical findings of FS, including partial seizures, prolonged seizures, multiple seizures during the same illness, and 30-min or longer prolonged postictal impairment of consciousness (PPIC), were analyzed by multiple logistic regression. A total of 215 patients (47 influenza A and 168 non-influenza patients) were enrolled in the study. Age was significantly higher in the influenza A group (39.85+/-22.16 months vs. 27.51+/-17.14 months, P<0.001). Of 42 patients aged 48 months or older, which corresponded to the 80th percentile for age, 15 (35.7%) were influenza A patients, with a significantly higher incidence of such patients than in the subgroup of patients aged 47 months or younger (32/173, 18.5%) (P=0.015). On multiple logistic regression analysis, influenza A was independently associated with PPIC (odds ratio: 4.44, 95% confidence interval: 1.52-12.95, P=0.006), but not with other atypical findings. The positive association of influenza A with PPIC suggests that influenza may affect state of consciousness at the same time that it induces seizures with fever.

TWO CASES OF HYPONATREMIC-HYPERTENSIVE SYNDROME IN CHILDHOOD WITH RENOVASCULAR HYPERTENSION

We report two children with renovascular hypertension and fibromuscular dysplasia. They initially presented with severe hyponatremia, hypokalemia, polyuria, and transient proteinuria. This combination of symptoms is known to occur in patients with renovascular and malignant hypertension, and is known as hyponatremic-hypertensive syndrome (HHS), although it is considered rare in children. Since in both of our patients, the renal arterial stenosis was very severely or almost totally occlusive, we could not perform percutaneous transluminal renal artery angioplasty, and therefore nephrectomy was the only option. A histological study showed partial or complete occlusion with intimal hyperplasia and medial fibroplasia of intrarenal arteries such as the interlobular arteries. Conclusion: Both patients showed rapidly progressive renovascular hypertension and loss of function of the affected kidney. In order to preserve renal function in such cases, early invasive intervention appears to be necessary.

Inhibition of matrix metalloproteinase-9 activity by trandolapril after middle cerebral artery occlusion in rats.

We investigated whether an angiotensin-converting enzyme (ACE) inhibitor could inhibit matrix metalloproteinase (MMP) activities in cerebral infarct lesions after middle cerebral artery occlusion (MCAO) in rats. After placebo or trandolapril (5 mg/kg per day) was administered orally for 7 days, we permanently occluded the right middle cerebral artery. ACE activity in extracts from the infarct side of placebo-treated rats was significantly higher than that in extracts from the non-infarct side from 5 days after MCAO, though they did not differ at 1 day. ACE activities in extracts from both hemispheric segments in the trandolapril-treated group were significantly decreased compared with those in the placebo-treated group before MCAO, and this significant reduction persisted even at 7 days after MCAO. In the placebo-treated group, MMP-9 and MMP-2 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO, respectively. Trandolapril treatment significantly reduced MMP-9 and MMP-2 activities to 68.5% and 53.2%, respectively. Seven days after MCAO, the ratios of infarct areas to the hemispheric sectional areas in placebo- and trandolapril-treated rats were 55.4±2.1% and 30.9±2.9%, respectively, and this difference was significant. Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril-treated rats. Cumulative survival in trandolapril-treated rats was significantly increased compared with that in placebo-treated rats. Thus, the inhibition of MMP-9 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia.

Second-Stage Palliation After Bilateral Pulmonary Artery Bands for HLHS and its Variants—Which is Better, Modified Norwood or Norwood Plus Bidirectional Glenn?

Background. The purpose of this study was to evaluate the surgical outcomes and pulmonary artery (PA) development associated with a new strategy wherein the modified Norwood (N) procedure is performed at 1-2 months after bilateral pulmonary artery banding (PAB). Methods. Between January 2008 and February 2010, 16 patients underwent Norwood-type operation after previous bilateral PAB. For analysis, patients were divided into two groups. Group I (n = 11) underwent modified Norwood procedure with either right modified Blalock Taussig (RMBT) shunt (n = 4) or right ventricle to pulmonary artery (RV-PA) conduit (n = 7). Group II (n = 5) underwent Norwood procedure plus bidirectional Glenn anastomosis. Diagnoses were hypoplastic left heart syndrome in 6 and its variants in 10. Results. There was no surgical death and no late death. Pulmonary artery interventions were performed at the time of the Norwood procedure in 27% in Group I and in 100% in Group II (p < 0.05). Additional PA interventions were performed during the period of follow-up in 4 cases in Group I (36.4%), and in 4 cases in Group II (80.0%). Additional Blalock Taussig shunts were performed in 7 patients, resulting in significant increase in PA index. In all, four patients have reached total cavopulmonary connection, and one has undergone biventricular repair. Eight patients in Group I and one patient in II Group reached bidirectional Glenn anastomosis. In Gp II, two patients showed LPA narrowing or obstruction with PA index of 80 ± 12 mm2/m2. Conclusions. Regarding the second-stage palliation after bilateral PAB, modified Norwood procedure with either RMBT or RV-PA conduit has some advantages compared with Norwood plus BDG with respect to subsequent pulmonary artery development. Additional BT shunt may contribute to PA development, even in the patients with Norwood procedure with RV-PA conduit.

Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease.

BACKGROUND Matrix metalloproteinase (MMP)-9 is thought to be involved in coronary artery aneurysms (CAAs) in patients with Kawasaki disease (KD); however, MMP-9 inhibitors are not used clinically. This study investigated whether the angiotensin-converting enzyme (ACE) inhibitor captopril could inhibit serum MMP-9 activity using serum from KD patients in an in vitro experiment. METHODS In 7 KD patients, serum MMP-9 activity was measured using the MMP-9 assay kit 3 times: before and after intravenous immunoglobulin (IVIG) treatment, and during the convalescent phase. The effect of captopril on MMP-9 activity was also assessed using serum obtained before IVIG treatment. RESULTS Serum MMP-9 activity was significantly higher during the pre-treatment phase than during the post-treatment and convalescent phases. MMP-9 activity during the pre-treatment phase was dose-dependently inhibited by captopril, and the IC(50) for MMP-9 was 500nM. The potency of captopril for MMP-9 inhibition was comparable to that for ACE inhibition. CONCLUSION ACE inhibitor may be effective for preventing CAA formation in KD patients, especially IVIG non-responders.

Measurement of Aortic Valve Coaptation and Effective Height Using Echocardiography in Patients with Ventricular Septal Defects and Aortic Valve Prolapse

Decreased coaptation height in adults has been identified as a marker of early valve failure. We evaluated aortic valve coaptation and effective height in healthy children and in children with a ventricular septal defect (VSD) with aortic cusp prolapse (ACP), using echocardiography. We included 45 subjects with VSD with ACP, 27 did not develop aortic regurgitation (AR) by ACP and 18 developed AR by ACP, and 83 healthy children as controls. Aortic root anatomy was estimated using the parasternal long-axis view. We measured the diameter of aortic valve (AV), coaptation height (CH), and effective height (EH) of the aortic valve. We defined the ACH (CH/AV ratio) and AEH (EH/AV ratio) indices as follows:

Aortopathy in an Adult With Tricuspid Atresia and Left Ventricular Non-Compaction After Fontan Procedure

\text{ACH }\!\!~\!\!\text{ index}\left( \text{ }\!\!\%\!\!\text{ } \right)\text{= }\!\!~\!\!\text{ }\frac{\text{CH}}{\text{AV}}\text{ }\!\!\times\!\!\text{ 100, AEH }\!\!~\!\!\text{ index}\left( \text{ }\!\!\%\!\!\text{ } \right)\text{= }\!\!~\!\!\text{ }\frac{\text{EH}}{\text{AV}}\text{ }\!\!\times\!\!\text{ 100}