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To clarify the histopathological characteristics of pulmonary hypertension (PH) in Japan, and to clarify the role of serotonin and endclthelin in monocrotaline induced PH, human histopathologiical studies and experimental studies were carried out. An epidemiological study based on the Annual of the Pathological Autopsy Cases in Japan, and a morphological study on autopsy cases of congenital heart disease and idiopathic PH were performed. Plasma levels of serotonin and endothelin, vascular responsiveness to serotonin, and the effects of a selective serotonin antagonist, DV-7028, were investigated after monocrotaline injection. Plexogenic pulmonary arteriopathy was prevalent, and recurrent pulmonary thromboembolism and pulmonary veno-occlusive disease extremely rare among primary pulmonary hypertension in Japan. In secondary PH, systemic lupus erythematosus and mixed connective tissue disease were frequent and showedl particularly severe intimal and medial thickening. After an injection of monocrotaline, plasma serotonin and endotheliii levels were raised, and pulmonary arteries showed hyperreactivity to serotonin. DV-7028 (5-HT2 receptor antagonist) attenuated the rise in pulmonary artery pressure and the various effects of monocrotaline. There may be some genetic difference between PH in Japan and other countries. Roles far serotonin and endothelin in the initiation and progression of monocrotaline induced PH are suggested.

An autopsy case of a 74-year-old man suffering from edema in the legs and diagnosed as protein-losing enteropathy due to intestinal lymphangiectasia is presented. He underwent a radical operation and radiotherapy for esophageal carcinoma at age 65 years and the onset of protein-losing enteropathy was at age 70. Postmortem examination disclosed widespread abnormalities of the duodenal and small intestinal lymphatics and mesenteric lymph node fibrosis. The mucosal lymphatic capillaries were markedly dilated. In the submucosal and serosal layers, the lymphatic vessels showed marked dilatation in some areas and fibrous occlusion with very thick muscle layers in others. All these lymphatic changes were presumed to be attributable to a reactive process secondary to lymph congestion, which it is suggested, was caused by the mesenteric lymph node fibrosis.

The pulmonary vasculature exhibits various morphological changes in patients with pulmonary hypertension (PH). Among them, the plexiform lesion is one of the most characteristic vascular lesions, although nothing is known about the molecular mechanisms of its formation. In the present study, the expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific angiogenic mitogen, and its receptors, fms-like tyrosine kinase (Flt-1) and kinase insert domain-containing receptor (KDR), in the lungs of five cases with PH, were examined. By in situ hybridization, VEGF expression was found in modified smooth muscle cells inside the plexiform lesions as well as in medial smooth muscle cells of the arteries adjacent to the lesions. The expression of Flt-1 mRNA was observed in endothelial cells of the arteries adjacent to the plexiform lesions, while KDR mRNA was expressed in the endothelial cells inside the plexiform lesions. VEGF was immunolocalized to the endothelial cells expressing its receptors as well as the modified smooth muscle cells producing VEGF. These results demonstrate that VEGF and its receptors are upregulated with a close correlation to the plexiform lesions, and suggest that VEGF expressed by smooth muscle cells may activate the endothelial cells to form the plexiform lesions.

Rheumatoid nodule is a frequent and characteristic extra-articular manifestation of rheumatoid arthritis (RA). Its involvement of central nervous system is a rare occurrence with only a few reported cases. A 78-year-old man with severe arthritis showing the formation of rheumatoid nodule-like granulomas in the dura and subarachnoid space along with the spleen is presented. The characteristic morphological finding of the granulomas was the presence of neutrophils and the absence of definite fibrinoid necrosis, which differed from the typical features of rheumatoid nodules previously described. The diagnosis should be based on the exclusion of diseases that may cause similar granulomatous reactions including infectious diseases. Additionally, there was systemic necrotizing vasculitis in the dura and multiple cerebral infarcts, although the association between vasculitis and cerebral infarcts was not clear.

A murine autosomal recessive mutant named twy (tiptoe walking-Yoshimura) mouse showing multiple osteochondral lesions including ankylosis of the vertebral column and limb joints underwent sequential histopathological analysis of posterior limb joint lesions and intervertebral disc lesions. In the articular cartilage, a decrease in alcian blue-positive extracellular matrix and the presence of degenerated collagen fibers were found at the age of around 4-8 weeks. Calcium deposits in the articular cartilage were found at that time and later in the articular space and synovial tissue. Calcium deposits were also found in the intervertebral discs at 4 weeks. Using electron microscopy, some of the crystals were seen inside small vesicles. In both joints, degeneration of, and calcium deposition in, the articular cartilage progressed with age, finally producing bony ankylosis. These histological observations suggest that calcification and degeneration of the articular cartilage are the major factors in the pathogenesis of joint disorders in the twy mouse, and this mutant mouse provides a good model for studying the process and mechanism of osteoarthritic lesions, destructive arthritis and ankylosis.

Two autopsy cases of granulomatous aortitis associated with necrotizing angiitis and glomerulonephritis were reported. Case 1 was a 31 year-old female and a diagnosis of typical Takayasu's arteritis was made. Case 2 was a 64-year-old female. In the central portion of the aotlc media, granulomatous inflammation surrounding coagulation necrosis was observed. This aortitis is different from classical Takayasu's arteritis and is diagnosed as “unclassified” aortitis. The significance and inter-relationship of these lesions were discussed. Clinical and anatomical features of these two cases suggest some common background of Immune abnormalities.

A case of annulo-aortic ectasia was reported. The patient was a 44 year old Japanese female who expired shortly after the operative intervention against aortic aneurysm and aortic insufficiency. This is the first case of annulo-aortic ectasia reported in Japan. Histological findings of the resected aneurysm revealed pronounced cystic medial necrosis. At autopsy, similar medial necrosis was found in the remaining aorta, pulmonary artery and some of the major branches of the aorta. The aortic valve cusps also showed myxomatous accumulation of acid mucopolysaccharides and hypoplasia of annular connective tissue. The aortic ring was dilated with evidence of regurgitation. Problems related to pathologic findings were discussed with special reference to a forme fruste manifestation of Marfan's syndrome. We believe cases, such as presented here, should not be considered as a forme fruste of Marfan's syndrome with the present knowledge of the disease, in spite of the morphologic similarity of lesions in our case with those described in classical Marfan's syndrome.