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It is generally accepted that chronic thromboembolic pulmonary hypertension (CTEPH) results from pulmonary emboli originating from deep vein thrombosis. However, this consensus opinion has been challenged, and the concept that some aspects of CTEPH exacerbation might result from a small-vessel disease leading to secondary thrombosis has been suggested. In addition to the effect of recurrent thrombo-embolism, a number of lines of clinical evidence indicate that progressive worsening is contributed to by remodeling in the small pulmonary arteries. Histopathological studies of the microvascular changes in CTEPH have identified vascular lesions similar to those seen in idiopathic pulmonary arterial hypertension (IPAH). Especially in in vitro and ex vivo experiments, pulmonary artery endothelial cells (ECs) in pulmonary hypertensive diseases are suggested to exhibit an unusual hyperproliferative potential with decreased susceptibility to apoptosis, indicating that dysfunctional ECs may contribute to the progression of the diseases. Although the degree and mechanisms of EC dysfunction as a contributor to CTEPH are unclear, EC dysfunction may occur in small arteries. Indeed, the cells stimulated by the microenvironment created by the unresolved clot may release substances that induce EC dysfunction. The EC dysfunctions in CTEPH may lead to disorders of the anti-coagulation properties in ECs and may result in additional clots in situ. Moreover, these may lead to the progression, not only of distal thrombus, but also of proximal clotting. This article reviews the pathobiological concepts of CTEPH and explains a crosstalk between EC dysfunction and in situ thrombi which may contribute to the vascular lesions of CTEPH.

The patient was a 34-year-old man, who was referred to our hospital because of abnormal shadows in the right lower lung field on a chest radiograph during a medical screening. Chest computed tomography (CT) showed a pulmonary arteriovenous fistula 23 x 17 mm in size in the anterior basal segment of the right lung, together with a single artery and single vein. He had no symptoms and did not have Osler-Weber-Rendu syndrome. Coil embolization was performed in order to decrease the risk of complications associated with right-to-left shunting. Transcatheter embolization using interlocking detachable coils and detachable fibered coils was successfully performed without severe complications. Then, 320-row multidetector CT revealed that the blood flow from the pulmonary artery disappeared just after coil embolization, the blood flow from the pulmonary vein flowed backward, and the fistula was contrasted. The fistula had almost completely disappeared 8 months after embolization. We confirmed that blood flows were interrupted by 320-row CT and pulmonary angiography. 320-row CT was useful for the evaluation of pulmonary arteriovenous fistula and coil embolization.

Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of "reverse remodeling" (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling.

We report a case of a 70-year-old man with chronic thromboembolic pulmonary hypertension (CTEPH) in whom bronchial asthma had been clinically diagnosed and treated, and who showed remarkable improvement by pulmonary endarterectomy. He had dyspnea on exertion and had been clinically treated for bronchial asthma for 15 years. However, his symptoms did not improve after oral and inhaled corticosteroid therapy, and he had dyspnea at rest. CTEPH was suspected by echocardiography and computed tomography (CT) and he was admitted to our hospital. Perfusion scans showed multiple segmental perfusion defects with normal ventilation study, and contrast-enhanced CT showed intramural thrombi in both pulmonary arteries. Right cardiac catheterization revealed a mean pulmonary arterial pressure of 70 mm Hg and pulmonary vascular resistance of 1699 dyn.s.cm(-5) with chronic thromboembolic findings on pulmonary angiography. After surgery his pulmonary hemodynamics and symptoms significantly improved. CTEPH is rarely diagnosed at the initial visit because the only symptom is dyspnea on exertion, and it is often misdiagnosed as other respiratory diseases. But it is important to suspect and diagnose CTEPH in patients with unexplained dyspnea because this disease can be cured by surgery.

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.

A 60-year-old man was admitted to our hospital complaining of back pain and bloody sputum. Chest CT scan showed characteristic multiple small nodules with central dense opacity and surrounding faint opacity, suggesting lesions with hemorrhage. Bone scintigram and MRI revealed multiple osteolytic lesions in pelvis and lumbar spine. Biopsy of the bone lesion established a diagnosis of angiosarcoma. Chemotherapy with paclitaxel and palliative radiotherapy for the bone were initiated. Pulmonary metastases dramatically diminished after 4 courses of paclitaxel treatment. After eight weeks, the tumor recurred. Salvage chemotherapy of weekly administration of docetaxel yielded limited effects. The patient died of cancer one year after treatment initiation.

Severe pulmonary hypertension (PH) is characterized by complex precapillary arteriolar lesions, which contain phenotypically altered smooth muscle (SM) and endothelial cells (EC). We have demonstrated that VEGF receptor blockade by SU5416 {3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin 2-one} in combination with chronic hypoxia causes severe angioproliferative PH associated with arterial occlusion in rats. We postulate that endothelial-mesenchymal transdifferentiation can take place in the occlusive lesions and that endothelium-derived mesenchymal cells can further differentiate toward a SM phenotype. To examine this hypothesis, we incubated human pulmonary microvascular endothelial cells (HPMVEC) with SU5416 and analyzed these cells utilizing quantitative-PCR, immunofluorescent staining and flow cytometry analysis. In vitro studies in HPMVEC demonstrated that SU5416 suppressed PGI2S gene expression while potently inducing COX-2, VEGF, and TGF-beta1 expression; and caused transdifferentiation of mature vascular endothelial cells (defined by Dil-ac-LDL, Lectin and Factor VIII) to SM-like (as defined by expression of alpha-SM actin) "transitional" cells, coexpressing both endothelial and SM markers. SU5416 expanded the number of CD34 and/or c-kit positive cells and caused transdifferentiation of CD34 positive cells but not negative cells. In conclusion, our data show that SU5416 generated a selection pressure that killed some EC and expanded progenitor-like cells to transdifferentiate to SM-like and neuronal-like cells.

Background: Substantial evidence has disclosed that some cytotoxic agents have complex activities in influencing signal transduction pathways in cells., Materials and Methods: cDNA microarray analysis was performed after exposing a human squamous cell carcinoma cell line, RERF-LC-AI, to low-dose cisplatin for 5 days. Up-regulated gene expressions were suppressed by small interfering RNA to investigate phenotypic alteration of the cells., Results: Among 30,000 genes screened, 42 genes showed increases or decreases in expression of more than 2-fold with cisplatin treatment. They included genes with functions involved in apoptosis, cell cycle regulation and DNA metabolism/repair. Suppression of the 5 most significantly altered genes by small interfering RNA resulted in partly reduced apoptosis without altering cytotoxicity of cisplatin., Conclusion: Besides direct cytotoxic effects on cells, cisplatin may have indirect effects involving drug resistance, and synergistic effects with other agents.

We have previously hypothesized that the development of severe angioproliferative pulmonary hypertension is associated with not only initial endothelial cell (EC) apoptosis followed by the emergence of apoptosis-resistant proliferating EC but also with proliferation of vascular smooth muscle cells (VSMC). We have demonstrated that EC death results in the selection of an apoptosis-resistant, proliferating, and phenotypically altered EC phenotype. We postulate here that the initial apoptosis of EC induces the release of mediators that cause VSMC proliferation. We cultured EC in an artificial capillary CellMax system designed to simulate the highly efficient functions of the human capillary system. We induced apoptosis of microvascular EC using shear stress and the combined VEGF receptor (VEGFR-1 and -2) inhibitor SU-5416. Flow cytometry for the proliferation marker bromodeoxyuridine showed that serum-free medium conditioned by apoptosed EC induced proliferation of VSMC, whereas serum-free medium conditioned by nonapoptosed EC did not. We also show that medium conditioned by apoptosed EC is characterized by increased concentrations of transforming growth factor (TGF)-beta1 and VEGF compared with medium conditioned by nonapoptosed EC and that TGF-beta1 blockade prevented the proliferation of cultured VSMC. In conclusion, EC death induced by high shear stress and VEGFR blockade leads to the production of factors, in particular TGF-beta1, that activate VSMC proliferation.

Background: We tested the feasibility of hyperthermia combined with concurrent radiotherapy (thermoradiotherapy) for pain relief and local control of non-small cell lung cancer (NSCLC) invading to the chest wall., Methods: Thirteen patients with advanced NSCLC (eight stage IIIB and five stage IV) and severe pain caused by chest wall invasion of tumor were treated with thermoradiotherapy. During the conventional fractionated radiotherapy period, 8-MHz radiofrequency capacitive hyperthermia was administered once or twice per week for a total of three to nine treatment sessions. Pain relief, objective tumor response, thermometry, and toxicity were evaluated., Results: Twelve of the 13 patients (92%) experienced satisfactory pain relief, and objective tumor shrinkage was observed in 11 of the 13 patients (85%), including complete regression in two. The thermometry parameters of minimum and maximum intratumor temperatures, mean of all intratumor temperatures, and rate of the time during which intratumor temperature was 41 degrees C or higher were 37.6 +/- 0.8 degrees C, 42.4 +/- 0.7 degrees C, 40.3 +/- 0.3 degrees C, and 80.1 +/- 8.6%, respectively. Adverse reactions included local transient skin pain in three patients, but no major toxicity was observed., Conclusion: Concurrent thermoradiotherapy for chest wall invasion by advanced NSCLC was feasible, with tolerable toxicity, and it may be effective for pain relief and local tumor control. Further studies comparing thermoradiotherapy and radiotherapy alone for such patient populations are warranted.