Effects of a dual inhibitor of tumor necrosis factor-alpha and interleukin-1 on lipopolysaccharide-induced lung injury in rats: involvement of the p38 mitogen-activated protein kinase pathway

OBJECTIVE: Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653. DESIGN: Prospective, randomized study. SETTING: Animal research facility in a university. SUBJECTS: Male Sprague-Dawley rats weighing 200-270 g. INTERVENTIONS: All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs. MEASUREMENTS AND MAIN RESULTS: LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues. CONCLUSIONS: FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.     

Effects of a phosphate buffered extracellular (Ep4) solution in preservation and reperfusion injury in the canine liver

The Ep4 solution, a phosphate buffered extracellular-type solution, is effective in canine lung transplantation following a 96-hour hypothermic (4 degrees C) preservation. In this experiment, we used this solution for liver preservation followed by transplantation. We compared the Ep4 solution with the lactated Ringer's (LR) and the Collins' M (CM) solution (a phosphate buffered intracellular-type solution) in two studies, 1) 48-hour liver preservation, and 2) orthotopic liver transplantation after 5-hour preservation. In the preservation study, purine nucleoside phosphorylase (PNP) levels as a marker of endothelial damage, and alanine aminotransferase (ALT) levels were significantly lower in the livers immersed into the Ep4 solution than in those immersed into other solutions at 36 and 48 hours after preservation. Microscopically, the endothelial injury occurred 24 hours after preservation in the CM solution, and 36 hours after preservation in the LR and Ep4 solutions. In the transplantation study, serum PNP and ALT levels in the livers immersed in Ep4 solution showed a lower tendency compared with those in other solutions at the time of reperfusion, but the histological differences among three groups were not apparent. The present study suggests that the liver can be stored better for a longer time using Ep4 solution than using LR and CM solutions.     

Pleomorphic adenoma of the main bronchus in an adult treated using a wedge bronchiectomy

A 34-year-old woman had complained of dyspnea on exertion for 3 months and was found to have a volume loss of the left lung. A smooth, vascularized, whitish nodular mass obstructing the orifice of the left main bronchus was noted on bronchoscopy. We performed a deep wedge resection of the main bronchus, preserving the lung parenchyma. Histopathologically, the tumor specimen was compatible with pleomorphic adenoma. To our knowledge, only two cases of pleomorphic adenoma arising from the main bronchus have been reported in the English-language literature, and ours is the first report of lung-preserving surgery.     

Therapeutic Effects of Anti‐FGF23 Antibodies in Hypophosphatemic Rickets/Osteomalacia

X‐linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D‐resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti‐FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25‐dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium‐phosphate cotransporter and 25‐hydroxyvitamin‐D‐1α‐hydroxylase and a suppressed expression of 24‐hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.     

Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyposis and a predisposition for developing colorectal cancer. FAP is frequently complicated by extracolonic disease, but complications of leukemia are rare. We present the first case of FAP complicated by chronic myelogenous leukemia (CML) in a 38-year-old man. The patient had numerous adenomas in the colorectum and a family history compatible with FAP. He was diagnosed as having FAP in February 2000. Two years after the diagnosis, he developed leukocytosis with the Philadelphia chromosome abnormality, indicating complication with CML. Imatinib mesylate was administered for the treatment of CML, and hematologic and cytogenetic remission of CML was achieved in 6 months. Numerous polyps, 2 to 3 mm in diameter, observed in the rectum prior to the administration of imatinib, regressed in size, but not in number, after 1 year of treatment with imatinib. Eighteen months later, however, the polyps were enlarged. In this patient, imatinib administration led to the remission of CML and might also have been responsible for the temporary regression of adenomatous polyps of FAP.     

Vascular smooth muscle cell apoptosis induced by 7-ketocholesterol was mediated via Ca2+ and inhibited by the calcium channel blocker nifedipine

Previous reports indicate that 7-ketocholesterol (7KCHO) induces apoptosis of cultured human vascular smooth muscle cells (SMCs). We hypothesized that calcium channel blockers will inhibit SMC apoptosis induced by 7KCHO because caspase-3 activity is Ca2+ dependent and 7KCHO stimulates caspase-3 and SMC apoptosis. So, the protective effect of the calcium channel blocker nifedipine on SMC apoptosis induced by 7KCHO was investigated. When 7KCHO (50 micromol/L) was added to SMCs, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling was positive. DNA extracted from SMCs exposed to 7KCHO showed a ladder pattern on agarose electrophoresis. In the presence of extracellular Ca2+, the Ca2+ influx, caspase-3 activity, and fragmented DNA also increased in SMCs incubated with 7KCHO dose-dependently. However, in the absence of extracellular Ca2+, no effects of 7KCHO on caspase-3 activity and fragmented DNA were observed. In the presence of nifedipine, the 7KCHO-induced increases in Ca2+ influx, caspase-3 activity, and the amount of fragmented DNA decreased significantly. These results suggest that 7KCHO-induced apoptosis of SMCs is inhibited by calcium channel blockade, and that Ca2+ influx into cells mediated by 7KCHO plays an important role in 7KCHO-induced apoptosis.     

Inhaled foreign body overlooked for 25 years in an adult

A 30-year-old man was admitted to our hospital because of refractory pneumonia. He had been repeatedly hospitalized owing to pneumonia recurring in the left lower lung field and had a 7-day history of hemoptysis at the age of 11. Chest computed tomography demonstrated reduced volume of the left lower lobe with parenchymal consolidation. The patient preferred surgery as first-line treatment rather than other interventions because he had suffered from refractory pneumonia or local pleuritis for a long time. Left lower lobectomy was performed. The resected specimen revealed obstruction of the posterior basal segment bronchus in which a foreign body (FB) was found embedded in granulation tissue. The FB was a plastic air-pistol pellet. After further questioning, the patient remembered aspirating the pellet while playing with the pistol at the age of 5. When it is difficult to remove a long-standing intrabronchial FB, we recommend surgery.     

Two cases of stage IV gastric cancer responding to chemotherapy with S-1 or UFT

We report patients with advanced Stage IV gastric cancer responding to chemotherapy with S-1 or UFT. Case 1: The patient was a 59-year-old man with Stage IV gastric cancer because of CY 1. After surgery, chemotherapy with S-1 (100 mg/body/day) was performed for one year and 11 months. At present, 5 years and 5 months after surgery, this patient shows no signs of tumor recurrence. Case 2: The patient was a 68-year-old woman with Stage IV gastric cancer because of P 1. She was treated with 200 mg/day of UFT for one year and 9 months. At present, 5 years after surgery, she shows no signs of tumor recurrence. We considered that the longterm survival of such patients is attributable to chemotherapy with S-1 or UFT. The OPRT activity of the two cases was high, so chemotherapy with S-1 or UFT was thought to be effective for them.