Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice.

Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserine-mediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32%. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.

Histological evaluation of skeletonized internal thoracic artery using ForceTriad™.

BACKGROUND: The internal thoracic artery (ITA) is a useful graft for coronary artery bypass grafting. Skeletonization, a technique that uses an ultrasonic scalpel, is increasingly used. However, the cost of an ultrasonic scalpel is extremely high. The purpose of this study was to determine whether a new electrosurgical cautery device (ForceTriad™) is as effective as an ultrasonic scalpel. METHODS: Bilateral ITAs were harvested from eight pigs using the skeletonizing technique. The ITA on one side was harvested with an ultrasonic scalpel and on the other side using the ForceTriad™. Macroscopic and histological examinations were performed in sixteen ITAs. RESULTS: No significant differences in the time required for harvesting were observed. The macroscopic findings revealed no significant change in any of the samples. The histological findings showed that the degree of thermal injury was similar. The normal structure was maintained in all samples. The ForceTriad™ costs US$ 226.82 less per patient than the ultrasonic scalpel. CONCLUSION: The new electrosurgical cautery device ForceTriad™ was less expensive, but it was equally effective. It appears that skeletonization performed with the new device is equivalent to that performed with an ultrasonic scalpel.

[Mitral valve replacement in a patient with Sheehan's syndrome].

Sheehan' syndrome is caused by pituitary apoplexy occurring during parturition and results in hypopituitarism, adrenal insufficiency and hypothyroidism. A 66-year-old woman with Sheehan's syndrome had received corticosteroids and thyroid hormones for about 18 years. The patient underwent mitral valve replacement for mitral regurgitation. Intraoperatively, just after the initiation of cardiopulmonary bypass, hypotension and severe edema suddenly occurred. Crystalloid fluid was rapidly administered to increase intravascular volumes. Postoperatively the body weight increased by 9.4 kg. The patient was intubated for 64 hours, stayed in the intensive care unit (ICU) for 7 days and was discharged from hospital on the postoperative day 36. Careful perioperative hormone supplementation is necessary for patients with Sheehan's syndrome.

Plasma eotaxin level and severity of asthma treated with corticosteroid.

Our understanding of asthma severity was advanced by the identification of biomarkers which account for differences in lung function impairment. We tried to examine the effects of corticosteroid treatment on known correlates of asthma severity including peripheral eosinophil counts, total IgE, IL-5, and eotaxin Levels in plasma. We compared these biomarkers among groups of stable asthmatics categorized by the dose of corticosteroid (N: steroid-free, n = 25; L: low-dose inhaled, n = 27; MH: medium or high-dose inhaled, n= 19; O: inhaled plus oral, n= 8). Next we compared these markers and peak expiratory flow rate (PEFR) in unstable asthmatics before and after treatment with steroids (n = 22). Eotaxin levels in the O group were higher than those in the N and MH groups (P < 0.05). Logistic regression analysis demonstrated that plasma eotaxin level was correlated with the severity of asthma defined by treatment intensity (P = 0.01) and % FEV1 (P = 0.04) while the other markers were not. Eotaxin levels did not change after steroid treatment in unstable patients, whereas eosinophil counts decreased in parallel with PEFR. Among biomarkers of asthma severity studied, plasma eotaxin level was not significantly affected by corticosteroid treatment, and was associated with the severity even in the presence of steroid therapy.

Effects of lithium and purinergic compounds on the behavioral and physiological aspects of restraint stress in rats.

This study investigates the effects of lithium and caffeine on psychomotor activities, defecation, and gastric lesions induced by restraint stress. Rats exposed to restraint stress typically exhibited a biphasic response consisting of an initial hypermotility (such as tail-flipping, body-rolling, jaw movement, and vocalization) accompanied by defecation, and followed by hypomotility (decrease in motility) accompanied by gastric ulceration. Lithium chloride (150 micrograms, ICV; 50 and 100 mg/kg, IP) significantly attenuated these responses while N6-cyclohexyl adenosine (CHA; 1.5 micrograms, ICV; 0.3 mg/kg, IP), a potent adenosine A1 receptor agonist, attenuated the behavioral effects but potentiated the gastric ulceration. Caffeine (3 micrograms, ICV; 1.0 mg/kg, IP), an adenosine receptor antagonist, inhibited the effects of CHA in animals exposed to 3 h of stress, but aggravated the effects in animals exposed to 6-12 h of stress. These results suggest that caffeine consumption may produce supersensitivity of adenosine receptors, which potentiate the actions of adenosine or CHA. Lithium may modulate the effects of stress by indirectly inhibiting central adenosine receptor activity.

[Type A dissection caused by aortic cannulation during coronary artery bypass grafting; report of a case].

A 71-year-old woman who had severe stenosis in the origin of the left anterior descending coronary artery with large diagonal branch was scheduled for coronary artery bypass grafting (CABG). After harvesting of bypass conduits, aortic cannulation was performed into the ascending aorta. Immediately after insertion of the cannula, however, the ascending aorta changed to a bluish color. Epiaortic ultrasonography revealed aortic dissection. Replacement of the ascending aorta was carried out using circulatory arrest under deep hypothermia. The intimal tear was located at the cannulation site. After this procedure, scheduled CABG the left internal thoracic artery to the left anterior descending coronary artery and the saphenous vein graft to the diagonal branch was performed. The proximal site of the saphenous vein graft was anastomosed to the replaced graft. The postoperative course was uneventful. Rapid identification and appropriate surgical management are necessary to minimize patient morbidity and mortality.

[Aortic valve regurgitation associated with rheumatoid arthritis; report of a case].

We report a rare case of aortic regurgitation (AR) associated with rheumatic arthritis (RA). A 59-year-old female was brought to our hospital with cardiopulmonary arrest because of severe heart failure due to AR. After being treated for heart failure, aortic valve replacement was carried out with a Carpentier-Edwards 21 mm model. During operation, it was observed that all of the coronary cusps had become thickened and shortened. A part of the right coronary cusp near the commissure of the left coronary cusp was especially badly affected. Valve histology showed a typical degeneration pattern. The patient had an uneventful postoperative course. It appears likely that the aortic valve had become shortened during the recovery process from inflammation caused by RA. The use of bioprostheses is beneficial in RA patients with aortitis, gastric ulcers, etc., since they reduce dynamic stress and eliminate the need for use of anti-coagulants.

[Re-coronary artery bypass grafting necessitated by flow insufficiency of right internal thoracic artery; report of a case].

A 75-year-old woman required re-coronary artery bypass grafting due to flow insufficiency of the right internal thoracic artery (RITA). After the first operation, coronary angiography revealed a narrowed RITA. Myocardial ischemia occurred when the native coronary artery was occluded by the catheter. A stringlike internal thoracic artery is probably unable to increase blood supply immediately in response to the demand created by acute obstruction of the recipient native coronary artery.

[Behavioral effects of chronic apomorphine, and D-1/D-2 dopamine receptor activities in rats].

The present study was conducted to investigate the effects of chronic treatment with apomorphine on yawning and stereotyped behaviors induced by apomorphine, and catalepic responses induced by haloperidol. Rats received apomorphine (1 mg/kg, sc), a direct dopamine D1/D2 agonist, or vehicle once a day for 21 days. The chronic treatment with apomorphine shifted to the right the dose response curve of yawning to administration of apomorphine, which preferentially activates presynaptic dopamine D-2 receptors (auto receptors) at low doses. Haloperidol (0.5 mg/kg, ip)-induced catalepsy mediated by the inhibition of postsynaptic D-2 receptors was unaltered. A subsequent challenge dose of apomorphine (5 mg/kg, ip) produced oral stereotyped behaviors such as sniffing, licking and biting in the vehicle-treated rats. Chronic apomorphine treatment produced significant enhancement of sniffing alone, which may be behavioral sensitization to apomorphine, and, in contrast, attenuated licking and biting, which depend on D-2 receptor activities. These phenomena lasted for at least 30 days. Sniffing might involve relatively increased stimulation of D-1 receptors, as compared with licking and biting. These results suggest that chronic apomorphine reduces presynaptic dopamine D-2 receptor activity, and as a consequence may induce long-lasting postsynaptic dopamine receptor (mainly D-1 receptor) activation.

[Effects of dopamine receptor agonists and antagonists on cocaine-induced behaviors in rats].

In this study, cocaine (5-20 mg/kg), an indirect dopamine agonist, increased locomotor activity and rearing accompanied with head circling and body shaking in a dose-dependent manner. A high dose of cocaine (40 mg/kg), meaning a toxic dose, slightly induced sniffing and licking. Both SCH23390, a D-1 receptor antagonist, and raclopride, a D-2 antagonist, inhibited all behaviors induced by cocaine, suggesting that the behavioral actions of cocaine may involve the activation of D-1 and D-2 receptors. Selective D-2 agonist quinpirole (0.1 and 1.0 mg/kg) inhibited hyperlocomotion induced by cocaine (20 mg/kg), but was replaced by the typical stereotyped behaviors such as sniffing at low dose (0.1 mg/kg), and licking and gnawing at high dose (1.0 mg/kg). SK & F38393, a selective D-1 agonist, in combination of cocaine did not induce these stereotyped behaviors which resulted in synergistic interaction of D-1 and D-2 receptor stimulation. These results suggest that the indirect stimulation of postsynaptic D-2 receptors by cocaine (20 mg/kg) was insufficient to induce stereotyped behaviors. The actions of cocaine on dopamine D-1 receptors seem to be more potent than that on D-2 receptors.

Evaluation of a new fiber-grating vision sensor for assessing pulmonary functions in healthy and COPD subjects.

Spirometry is practically the only tool to evaluate pulmonary functions. Other automatic systems comparable to spirometry are expected. A fiber-grating (FG) vision sensor is a non-contact respiratory monitoring system to detect changes in volumes by measuring the movement of laser spots on the body surface. We examined the contributions of the FG sensor to evaluating pulmonary functions. The FG sensor showed a linear correlation with spirometry in tidal volumes (TV) obtained from five controls (R = 0.98, P < 0.0001). We also showed agreement of TV between the two devices using Bland-Altman analysis. TV measured by the FG sensor were reproducible and applicable to distinct subjects. To detect airway obstruction, we performed forced expiration in controls (n = 16) and chronic obstructive pulmonary disease (COPD) patients (n = 18) with the FG sensor and spirometry. Forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity in COPD patients were lower than those in controls by the FG sensor. In addition, prolonged expiration in natural breathing by the FG sensor was related to airflow limitation by spirometry. The FG sensor was helpful to measure volume changes and to evaluate pulmonary functions in controls and patients with COPD. Its upcoming clinical applications are promising for simplicity and feasibility.

Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms.

The whole gene deletion CYP2A6*4, the defect of the main nicotine oxidase, contributes to limiting lifelong and daily cigarette consumption. However, the effects on smoking habits of CYP2A6*7 and *9, two major functional polymorphisms common in Asian populations, have not been reported. The present study examined the relationship between polymorphisms *4, *7 and *9 with the smoking habits of 200 Japanese smokers who visited the Keio University Hospital (Tokyo, Japan). The allele frequencies of *1 (wild type), *4, *7 and *9 were 52, 17, 11 and 20%, respectively. When the three polymorphisms were considered simultaneously, the percentages of homozygous wild type, heterozygote, and homozygous mutants and compound heterozygotes were 26.0, 52.5 and 21.5%, respectively. Homozygous mutants and compound heterozygotes (n = 43) smoked fewer cigarettes daily than heterozygotes (n = 105) and homozygous wild-type individuals (n = 52). Smokers with *7/*7, *9/*9 or *7/*9 had lower daily cigarette consumption than smokers with *1/*1. In conclusion, polymorphisms *4, *7 and *9 of CYP2A6 were detected in approximately three out of four Japanese smokers, and their daily cigarette consumption was genetically modulated by these functional polymorphisms.

Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema.

Protease-antiprotease imbalance due to genetic variation may be responsible for the development of pulmonary emphysema induced by smoking. Since matrix metalloproteinases (MMPs) have recently been suggested to play important roles in the pathogenesis of pulmonary emphysema, the association between the functional polymorphism of MMP-9 (-1562C/T) and the development of pulmonary emphysema was examined in 110 smokers and 94 nonsmokers in Japan. The T allele frequency was higher in subjects with distinct emphysema on chest CT-scans (n = 45) than in those without it (n = 65) (0.244 vs 0.123, P = 0.02). Logistic regression analysis demonstrated that the T allele is a risk factor for smoking-induced emphysema (odds ratio = 2.69, P = 0.02). DL(CO)/VA was lower (P = 0.02) and emphysematous changes were more conspicuous (P = 0.03) in subjects with C/T or T/T (n = 35) than in those with C/C (n = 75). These results suggest that the polymorphism of MMP-9 acts as a genetic factor for the development of smoking-induced pulmonary emphysema.

Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema.

BACKGROUND: Nicotine is responsible for smoking dependence and is mainly metabolised by CYP2A6. Several types of genetic polymorphism of CYP2A6 have been reported, but their relation to smoking habit and chronic obstructive pulmonary disease (COPD) phenotypes has not been fully clarified. METHODS: 203 current or ex-smokers (lifelong cigarette consumption (CC) >/=10 pack years) with subclinical and established COPD phenotypes were clinically evaluated and pulmonary function tests and a chest CT scan were performed (smoker group). The non-smoker group consisted of 123 healthy volunteers. CYP2A6 genotypes were determined in both groups. RESULTS: The percentage of subjects with a CYP2A6del allele (genotype D) was lower in heavy smokers (20.5%, n=88, CC >/=60 pack years) than in light smokers (37.4%, n=115, CC 10-59 pack years, chi(2)=6.8, p=0.01) or non-smokers (36.1%, n=122, chi(2)=6.0, p=0.01); lower in ex-smokers (20.7%, n=111) than in current smokers (41.3%, n=92, chi(2)=10.1, p<0.01); and lower in smokers with a high LAA (low attenuation area) score on the chest CT scan (18.4%, n=76, LAA >/=8.0) than in those with a low LAA score (37.0%, n=127, LAA <8.0, chi(2)=7.8, p<0.01). CONCLUSIONS: Subjects with the CYP2A6del allele tend not to be heavy habitual smokers but can be light habitual smokers. The CYP2A6del polymorphism may inhibit smokers from giving up smoking, but appears to function as a protective factor against the development of pulmonary emphysema independent of smoking habit.

[Left atrial pressure gradient and right heart failure secondary to compression of the left atrium by a huge ascending aortic aneurysm: a case report].

A 71-year-old man was admitted to our department with congestive heart failure on June 28, 1998. He previously had an aortic valve replacement because of aortic regurgitation probably due to annuloaortic ectasia in 1984. Thoracic aortic aneurysm was identified during the postoperative course. Magnetic resonance imaging showed a huge saccular ascending aortic aneurysm of 12 x 11.5 x 9.5 cm size, which had severely compressed the left atrium. Doppler echocardiography documented an accelerated flow (2.2 m/sec) in the left atrium in early diastole. The calculated pressure gradient was 19 mmHg. All pressures in the right heart system were elevated. This is the first case of pulmonary hypertension and right heart failure secondary to compression of the left atrium in a patient with thoracic aortic aneurysm.

Eotaxin and monocyte chemoattractant protein-1 in chronic eosinophilic pneumonia.

Chronic eosinophilic pneumonia (CEP) is characterized by chronic or recurrent pulmonary infiltrates with eosinophils, but the precise mechanism of eosinophil accumulation has not been fully elucidated. Eotaxin is one of the CC chemokines that selectively recruits eosinophils and contributes to the pathogenesis of allergic airway diseases including asthma, but its roles in pathogenesis of CEP have not been fully elucidated. The authors measured concentrations of eotaxin and other CC chemokines, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted, macrophage inflammatory protein-1alpha, and the eosinophil activating Th2 cytokine interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid from CEP patients (n=11), and compared these concentrations with those from control subjects (n = 6). The eotaxin (904 +/- 203 versus 29 +/- 7 pg x mL(-1), p = 0.0001), MCP-1 (194 +/- 57 versus 15 +/- 2 pg x mL(-1), p < 0.05), and IL-5 (7.8 +/- 2.0 versus 2.7 +/- 0.6 pg x mL(-1), p < 0.05) levels were significantly higher for cases with CEP in comparison to those serving as controls. Proportions of eosinophil and lymphocyte counts were greater in BAL fluid from CEP patients. Eotaxin and IL-5 levels correlated with the proportion of eosinophils in BAL fluid from CEP patients. MCP-1 correlated with the relative lymphocyte numbers. In short, eotaxin, interleukin-5, and monocyte chemoattractant protein-1 levels were higher in the BAL fluid of CEP patients and these levels may contribute to eosinophil and lymphocyte recruitment and activation in the airways as found with this disorder.