Effects of IS-741, a Synthetic Anti-Inflammatory Agent, on Bleomycin-Induced Lung Injury in Mice

Bleomycin (BLM)-induced lung injury consists of excessive inflammatory cell infiltration and fibrosis. IS-741 has been reported to be an anti-inflammatory drug through an inhibitory action on cell adhesion. In this study we investigated whether IS-741 could inhibit the progression of pulmonary fibrosis through inflammatory cell infiltration. Lung injury was induced in female C57BL/6 mice by intratracheal instillation of BLM. IS-741 was administered daily intraperitoneally. The hydroxyproline content and fluid content in the lung on Day 28 were significantly lower in the IS-741-treated mice. The histological degree of lung injury or fibrosis was reduced in IS-741-treated mice. Administration of IS-741 caused significant reduction in the absolute number of total cells, monocyte chemoattractant protein (MCP)-1, and cysteinyl leukotriene (cysLTs) levels in bronchoalveolar lavage fluid on Day 7. Furthermore, the hydroxyproline content was significantly lower in IS-741-treated mice even though IS-741 was started on Day 14 after BLM instillation. Treatment with IS-741 had an inhibitory effect on BLM-induced lung injury and fibrosis via the repression of MCP-1 or cysLTs in this murine experimental model.     

The action of a novel vitamin D3 analogue, OCT, on immunomodulatory function of keratinocytes and lymphocytes

Abstract Topical vitamin D₃ has relatively recently been introduced for the treatment of psoriasis. Synthetic vitamin D₃ analogues with a high potential for inducing differentiation of cells, but with a low hypercalcemic effect have recently been developed. One such synthetic analogue of 1,25-dihydroxyvitamin D₃ (calcitriol), 22-oxacalcitriol (OCT), is a novel agent for the topical treatment of psoriasis. The activity of OCT in vitro was investigated and compared with that of a series of vitamin D₃ analogues as to their ability to inhibit murine T lymphocyte proliferation stimulated by con-A, to suppress IL-6 and IL-8 production by keratinocytes stimulated with IL-1α and TNFα, and to inhibit AP-1- and NFκB-dependent reporter gene expression. OCT inhibited the proliferation of lymphocytes and suppressed IL-8 and IL-6 production by keratinocytes to the same extent as the other vitamin D₃ analogues. It also inhibited AP-1- and NFκB-controlled luciferase activity to the same extent as the other vitamin D₃ analogues, which demonstrates its mechanism of action in the suppression of inflammatory processes. Received: 26 January 1999 / Received after revision: 10 June 1999 / Accepted: 11 June 1999     

The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression

Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). TP is overexpressed in various tumors and plays an important role in angiogenesis, tumor growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP. A novel, specific TP inhibitor, TPI, inhibits angiogenesis induced by overexpression of TP in KB/TP cells (human KB epidermoid carcinoma cells transfected with TP cDNA), as well as the growth and metastasis of KB/TP cells in vivo. 2-deoxy-D-ribose, the degradation product of thymidine generated by TP activity, has both angiogenic and chemotactic activity. Both 2-deoxy-D-ribose and TP inhibit a hypoxia-induced apoptotic pathway. These findings suggest that 2-deoxy-D-ribose is a downstream mediator of TP function. 2-deoxy-L-ribose, a stereoisomer of 2-deoxy-D-ribose, inhibits the promotion of angiogenesis, tumor growth and metastasis by TP. Although the mechanism of the action of 2-deoxy-D-ribose is still unknown, 2-deoxy-L-ribose may inhibit the physiological activities of 2-deoxy-D-ribose, and consequently those of TP. Inhibition of TP activity and function appears to be a promising approach for the chemotherapy of various tumors.     

Acute calcific tendinitis of the gluteus medius: a case report with serial magnetic resonance imaging findings

A case of calcific tendinitis of the gluteus medius is presented. Calcification was evident in the soft tissue adjacent to the greater trochanter on plain radiographs. On the initial magnetic resonance images (MRI), inflammatory edematous change was detected not only in the gluteus medius but also in the bone marrow of the greater trochanter, corresponding to the painful area. Three months later, calcification disappeared on plain radiographs and the femur showed normal signal intensity on MRI. Initial MRI excluded other diseases including infection and bone tumor, and serial MRI confirmed that the change in extraosseous and intraosseous findings were in accordance with self-limiting clinical symptoms.     

Therapeutic antagonists and the conformational regulation of the beta2 integrins

The beta2 integrins are validated therapeutic targets for inflammatory disorders. Two distinct mechanistic classes of small molecule inhibitors, termed alpha I allosteric and alpha/beta I-like allosteric antagonist, have recently been developed. The alpha I allosteric antagonists bind underneath the C-terminal helix of the I domain and stabilize the I domain in the inactive closed conformation. By contrast, the alpha/beta I-like allosteric antagonists bind to the beta2 I-like domain MIDAS and disrupt conformational signal transmission between the I and the I-like domain, leaving the I domain in a default inactive form. Furthermore, the two classes of the antagonists have opposite effects on integrin conformation; the alpha I allosteric antagonists stabilize the bent conformation, whereas the alpha/beta I-like allosteric antagonists induce the extended conformation with inactive I domain. The small molecule antagonists to the beta2 integrin highlight the importance of the structural linkages within and between integrin domains for transmission of the conformational signals and regulation of the overall conformation.     

Therapeutic antagonists and conformational regulation of integrin function

Integrins are a structurally elaborate family of adhesion molecules that transmit signals bi-directionally across the plasma membrane by undergoing large-scale structural rearrangements. By regulating cell-cell and cell-matrix contacts, integrins participate in a wide range of biological processes, including development, tissue repair, angiogenesis, inflammation and haemostasis. From a therapeutic standpoint, integrins are probably the most important class of cell-adhesion receptors. Recent progress in the development of integrin antagonists has resulted in their clinical application and has shed new light on integrin biology. On the basis of their mechanism of action, small-molecule integrin antagonists fall into three different classes. Each of these classes affect the equilibria that relate integrin conformational states, but in different ways.     

Factors related to malnutrition in patients with esophageal cancer.

Based on data indicating that decreases in body weight (BW), arm muscle circumference (AMC), and rapid-turnover proteins (RTPs) correlate with fatal septic complications after surgery for esophageal cancer, we examined possible factors contributing to protein-calorie malnutrition (PCM) in patients with this disease. Eight parameters of nutritional status were assessed. Associations between sex, age, stage of cancer, and degree of dysphagia and PCM were analyzed via multiple linear regression for 75 patients with esophageal cancer and 58 with gastric cancer. These four factors independently contributed to PCM in patients with esophageal cancer, whereas malignant tumor and age contributed to PCM in those with gastric cancer. The degree of dysphagia was related to decreases in serum albumin and RTP and weakly related to decreases in BW and AMC. Stage of cancer, age, and sex were associated with reductions in albumin and/or RTP. Thus, we conclude that simple starvation, malignant tumor, age, and sex contribute to PCM and probably to the occurrence of fatal septic complications postoperatively.     

A study on the effect of water intake of umpires during a baseball game in a summer-heat environment

The purpose of this study was to examine the effect of umpires' intake of water during a summertime baseball game, on serum and urinary biochemical elements, body weight and physiological factors. Twenty-eight umpires were classified into two groups. Group W was composed of 14 umpires who had water while those who did not were group C. Group W had 250 ml of water that was cooled to about 5 degrees C after the 5th inning of the game. The game was played in the following environment: atmosphere temperature was 31 degrees C; wet-bulb temperature was 26 degrees C; blackglove temperature was 40 degrees C; the velocity of the wind was 1.18 m/sec in bright sunshine on a hot and moist day. The results obtained were as follows. In group W, more body weight was lost than in group C, but statistically there was no significant difference. Urinary volume in group W became smaller than in group C, but statistically there was no significant difference. Water in blood increased in group W and decreased in group C but statistically there was significant difference. In both groups, oral temperature decreased, but only in group C was there a statistically significant difference. Although the intake of water increased the volume of perspiration, it did not dilute the concentrated blood, suppress the rise of body temperature, or result in a rise of low blood pressure.