Tomohiro Kurihara

Neutrophil-Derived Matrix Metalloproteinase 9 Triggers Acute Aortic Dissection

Background— Acute aortic dissection (AAD) is a life-threatening vascular disease without effective pharmaceutical therapy. Matrix metalloproteinases (MMPs) are implicated in the development of chronic vascular diseases including aneurysm, but the key effectors and mechanism of action remain unknown. To define further the role of MMPs in AAD, we screened circulating MMPs in AAD patients, and then generated a novel mouse model for AAD to characterize the mechanism of action. Methods and Results— MMP9 and angiotensin II were elevated significantly in blood samples from AAD patients than in those from the patients with nonruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, &bgr;-aminopropionitrile monofumarate. AAD was developed successfully in the thoracic aorta by angiotensin II administration to &bgr;-aminopropionitrile monofumarate-treated wild-type mice, with an incidence of 20%, 80%, and 100% after 6, 12, and 24 hours, respectively. Neutrophil infiltrations were observed in the intima of the thoracic aorta, and the overexpression of MMP9 in the aorta was demonstrated by reverse transcription polymerase chain reaction, gelatin zymography, and immunohistochemistry. The incidence of AAD was reduced significantly by 40% following the administration of an MMP inhibitor and was almost blocked completely in MMP−/− mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of anti-granulocyte-differentiation antigen-1 (anti-Gr-1) antibody also significantly decreased the incidence of AAD. Conclusions— These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II.

Antimicrobial-susceptible patterns of Staphylococcus aureus isolated from surgical infections: A new approach

Our goal was to analyze minimum inhibitory concentration (MIC) data for Staphylococcus aureus isolated from surgical infections (SIs) and to look for correlations among the clinically available antimicrobials that were tested. Clinical isolates from SIs were collected by a multicenter surveillance group involving 34 institutions in Japan. During the period April 1998 to March 2007, 312 strains of S. aureus [71 methicillin susceptible (MSSA) and 241 methicillin resistant (MRSA)] were consecutively obtained from these institutions. MIC data for 18 clinically available antimicrobial agents [ABPC, CEZ, CTM, CMX, CPR, FMOX, CFPM, CZOP, IPM, MEMP, GM, ABK, MINO, CLDM, FOM, LVFX, VCM, and TEIC (abbreviations defined in Tables 2 and 3)] against these isolates was analyzed using a principal component analysis (PCA). PCA revealed that four principal components explained 71.1% of the total variance. The first component consisted of major contributions from MEPM and IPM. The second component consisted of major contributions from MINO. These two-first axes, which were strong and explained 54.2% of the total variance, were able to classify the clinical isolates into four clusters. Furthermore, the proportion of the four clusters provided the characteristics of the S. aureus that were clinically isolated at each institute. PCA is a clinically applicable method for analyzing MIC patterns. Such analyses might contribute to the establishment of a practical classification of antimicrobial agents and to the identification of the characteristic antimicrobial resistance patterns at each institute.