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Background: Recent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group. Objectives: The authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema. Methods: We categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders. Results: Among 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis. Conclusions: This study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541).
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Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, ß1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.
Subject(s)
Endothelial Cells , Lung Diseases , Humans , Endothelial Cells/metabolism , Leukocytes, Mononuclear , Adhesiveness , Endothelium, Vascular/metabolism , Cells, Cultured , Cytokines/metabolism , Lung , Asialoglycoprotein Receptor/metabolismABSTRACT
CASE PRESENTATION: A 65-year-old man experienced a cough and mild hemoptysis suddenly one morning. He was prescribed tranexamic acid and carbazochrome salicylate by the local clinic at the first visit, and his hemoptysis stopped. However, 2 days later, he experienced recurrent hemoptysis that was prolonged intermittently. He had slight dyspnea and chest discomfort, but no other symptoms, such as sputum, fever, or chest pain. He was referred to our hospital for further assessment of hemoptysis. He had experienced mild hemoptysis of unknown causes 8 years earlier without recurrence until this episode. He had bronchial asthma that was treated with an inhaled corticosteroid and hypertension and hyperuricemia that were untreated with medication. He had no known allergies or family history of lung disease. He did not smoke. The patient denied alcohol consumption, any recent travel, or exposure to TB.
Subject(s)
Hemoptysis , Lung Diseases , Male , Humans , Aged , Hemoptysis/diagnosis , Hemoptysis/etiology , Tomography, X-Ray Computed/adverse effects , Dyspnea/etiology , Lung Diseases/diagnosis , Cough/diagnosis , Diagnosis, DifferentialABSTRACT
When Aspergillus, an ubiquitous, saprophytic fungus, is detected in respiratory tract specimens collected from chronic respiratory disease patients, it is important to determine whether it is a true infection or colonization. We investigated the usefulness of the Bio-Rad Platelia Aspergillus IgG (Platelia Aspergillus IgG) enzyme-linked immunosorbent assay (ELISA) method and the Aspergillus precipitin test to distinguish pulmonary aspergillosis from colonization. Between January 2017 and November 2021, 51 confirmed, untreated pulmonary aspergillosis (33 chronic pulmonary aspergillosis [CPA] and 18 allergic bronchopulmonary aspergillosis [ABPA]) and 77 colonization patients were included in this study. At first, the conventional cutoff value was utilized in assessing the validity of the two antibody tests for distinguishing pulmonary aspergillosis from colonization. The Platelia Aspergillus IgG cutoff value was then reevaluated to fit this situation. Finally, differences in test accuracy dependent on Aspergillus species were assessed for both antibody tests by comparing cases with Aspergillus fumigatus complex and those with non-fumigatus Aspergillus complex. Both antibody tests demonstrated significantly higher positive rates for pulmonary aspergillosis (P < 0.0001) than colonization. The cutoff value should be 15.7 arbitrary units (AU)/mL to best distinguish infection from colonization, which was higher than the conventional value of 10 AU/mL. The diagnostic sensitivity of Platelia Aspergillus IgG for the non-fumigatus Aspergillus complex was inferior to the A. fumigatus complex (P = 0.019). In conclusion, both Aspergillus antibody tests were valid to distinguish infection from colonization, although we should note the higher cutoff value for Platelia Aspergillus IgG and the lower sensitivity in cases of non-fumigatus Aspergillus infection. IMPORTANCE Pulmonary aspergillosis is the most common pulmonary fungal infection. However, Aspergillus is a ubiquitous, saprophytic fungus; it can be detected in respiratory specimens even in the absence of infection. Especially since Aspergillus is detected in respiratory specimens collected from patients with chronic respiratory disease, it is important to determine whether it is true infection or colonization. We investigated the validity of the Platelia Aspergillus IgG ELISA method and the Aspergillus precipitin test to distinguish pulmonary aspergillosis from colonization. Both antibody tests were considered useful in differentiating true infection from colonization in respiratory practice. The appropriate cutoff value for Platelia Aspergillus IgG was higher than the conventional value, and it was also noted that the sensitivity of both antibody tests for non-fumigatus Aspergillus complex was low. This study will be significant in real-world clinical practice of pulmonary aspergillosis using antibody tests in respiratory care.
Subject(s)
Aspergillosis, Allergic Bronchopulmonary , Pulmonary Aspergillosis , Humans , Precipitin Tests , Aspergillus , Pulmonary Aspergillosis/diagnosis , Aspergillosis, Allergic Bronchopulmonary/diagnosis , Antibodies, Fungal/analysis , Immunoglobulin G/analysis , Aspergillus fumigatusABSTRACT
Objective The incidence of tuberculosis in Japan has been decreasing in the overall population but is increasing in older patients ≥90 years old. A poor performance status due to underlying diseases makes it difficult for patients with tuberculosis to receive standard oral treatment. However, there is no consensus concerning alternative treatments. This study examined the treatments and outcomes of older patients with tuberculosis and a poor performance status and determined the limitations of tuberculosis treatment for them. Methods We retrospectively enrolled 121 older patients with tuberculosis and a performance status of 3 or 4 due to underlying diseases during their hospitalization between April 2015 and March 2017 at National Hospital Organization Tokyo National Hospital. We classified them according to the drug administration route (oral, enteral, and injection routes) on admission and compared the characteristics and prognoses among the three groups. Results There were 79 patients in the oral route group, 28 (35.4%) of whom died during hospitalization. Among the 15 patients in the enteral route group, 6 (40.0%) died. Among the 27 patients in the injection route group who received non-oral agents, 22 (81.5%) died. The prognosis of the injection route group was poor, with a median survival time of 21 days. Conclusion Treatment success cannot be expected with injection treatment in patients with a poor general condition because of complications. Although injection treatment may be a viable alternative treatment, its establishment as the standard treatment cannot be currently endorsed.
Subject(s)
Tuberculosis , Humans , Aged , Aged, 80 and over , Retrospective Studies , Tuberculosis/complications , Tuberculosis/drug therapy , Tuberculosis/epidemiology , Prognosis , Hospitalization , Japan/epidemiologyABSTRACT
BACKGROUND: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.MethodsâandâResults:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. CONCLUSIONS: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.
Subject(s)
Hypertension, Pulmonary , Lung Diseases, Interstitial , Respiration Disorders , Familial Primary Pulmonary Hypertension , Humans , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/drug therapy , Japan , Lung Diseases, Interstitial/complications , Lung Diseases, Interstitial/drug therapy , Prospective Studies , Respiration Disorders/complications , Respiration Disorders/drug therapyABSTRACT
BACKGROUND: There is no study on the predictive factors of recurrent haemoptysis after bronchial artery embolization (BAE) with the long-term outcomes in patients with bronchiectasis (BE). OBJECTIVES: To evaluate the long-term outcomes of BAE in BE patients without accompanying refractory active infection of mycobacteriosis and aspergillosis with analysis for the predictive factors of recurrent haemoptysis. METHODS: Data of 106 patients with BE who underwent BAE using coils between January 2011 and December 2018 were retrospectively reviewed. The cumulative haemoptysis control rate was estimated using Kaplan-Meier methods with log-rank tests to analyze differences in recurrence-free rate between groups based on technical success and failure, bacterial colonization status, number of BE lesions, and vessels embolized to bronchial arteries (BAs) or BAs + non-bronchial systemic arteries (NBSAs). RESULTS: Bacterial colonization was detected in approximately 60% of patients. Computed tomography showed bronchiectatic lesions with 2.9 ± 1.4 lobes. In the first series of BAE, embolization was performed in the BAs alone and BAs + NBSAs in 65.1 and 34.9% of patients, respectively, with 2.4 ± 1.4 embolized vessels in total. The median follow-up period was 1,000 (7-2,790) days. The cumulative haemoptysis control rates were 91.3, 84.2, 81.5, and 78.9% at 1, 2, 3, and 5 years, respectively. The haemoptysis control rates were higher in the technical success group than in the technical failure group (p = 0.029). CONCLUSIONS: High haemoptysis control rates for long-term periods were obtained by embolization for all visualized abnormal arteries, regardless of the colonization status, number of bronchiectatic lobes, and target vessels, irrespective of NBSAs.
Subject(s)
Bronchiectasis/therapy , Embolization, Therapeutic , Hemoptysis/therapy , Bronchi/diagnostic imaging , Bronchial Arteries/diagnostic imaging , Bronchial Arteries/microbiology , Bronchiectasis/complications , Bronchiectasis/microbiology , Computed Tomography Angiography , Hemoptysis/etiology , Humans , Kaplan-Meier Estimate , Recurrence , Retrospective Studies , Secondary Prevention , Treatment OutcomeABSTRACT
Molecular-targeted drugs (MTDs), such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors, are used to treat non-small-cell lung cancer (NSCLC). The incidence of rash caused by EGFR-TKIs and discontinuation of MTDs because of rash are issues. Rapid desensitization therapy (RDT) was performed in five patients who developed severe rash after introduction of MTDs and was successful in four, all of whom showed no rash relapse. RDT may thus be useful for treating rash in patients receiving MTDs for NSCLC.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Exanthema , Lung Neoplasms , Pharmaceutical Preparations , Anaplastic Lymphoma Kinase , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/genetics , Exanthema/chemically induced , Exanthema/drug therapy , Humans , Lung Neoplasms/drug therapy , Mutation , Neoplasm Recurrence, Local , Protein Kinase Inhibitors/adverse effectsABSTRACT
Ovarian cancer is a critically lethal gynecologic malignancy. More than 80% of patients with ovarian cancer have relapses within 5 years after initial treatment. However, recurrence from ovarian cancer more than 20 years later is extremely rare. We report a case of a 67-year-old female with mediastinal metastasis from ovarian cancer 29 years after initial gynecologic surgery and chemotherapy.
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Combined pulmonary fibrosis and emphysema (CPFE) is a common but under-recognized syndrome characterized with distinct profiles of both pulmonary fibrosis and emphysema. Pulmonary hypertension (PH) is particularly prone to develop as a common complication, leading to exercise limitation and worse prognosis of CPFE. Although the therapy of patients with PH from CPFE cannot be endorsed, an individual treatment may be considerable when accompanying severe PH. We report a case of a 71-year-old male with PH from CPFE, who improved pulmonary arterial compliance (PAC) and exercise capacity in response to pulmonary vasodilator.
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Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.
Subject(s)
Cell Proliferation/drug effects , Endothelial Cells , Hypertension, Pulmonary , Indoles/pharmacology , Muscle, Smooth, Vascular , Muscle, Smooth , Animals , Disease Models, Animal , Endothelial Cells/metabolism , Endothelial Cells/pathology , HEK293 Cells , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/physiopathology , Muscle, Smooth/metabolism , Muscle, Smooth/pathology , Muscle, Smooth/physiopathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Rats , Vascular Remodeling/drug effectsABSTRACT
Pulmonary hypertension (PH) due to lung diseases is classified as group 3 by the Dana Point classification. Given the basic pathophysiological conditions of group 3 lung diseases and the previously well-known concept of hypercapnic pulmonary vasoconstriction, chronic hypercapnia besides alveolar hypoxia might be another causative factor to increase mean pulmonary arterial pressure (PAm). Two hundred twenty-five subjects with chronic pulmonary diseases were assessed by a right heart catheterization and blood gas parameters. The subjects were classified into the following 4 groups: Hypercapnic Hypoxia (HCHX), Hypercapnic Normoxia (HCnx), Normocapnic Hypoxia (ncHX), and Normocapnic Normoxia (ncnx). Compared with ncnx, the HCHX, HCnx and ncHX groups all showed significantly higher PAm and met the criteria of borderline PH. Multiple regression analysis showed that PaCO2, as well as SaO2, was an independent variable for PAm. Given the poor prognosis with borderline PH, the elimination of excess pulmonary carbon dioxide in hypercapnia could be a considerable treatment strategy in chronic pulmonary disease.
Subject(s)
Hypercapnia/physiopathology , Hypertension, Pulmonary/physiopathology , Adolescent , Adult , Aged , Arterial Pressure , Blood Gas Analysis , Chronic Disease , Female , Humans , Hydrocarbons, Chlorinated/metabolism , Male , Middle Aged , Oxygen/metabolism , Retrospective Studies , Young AdultABSTRACT
Cutaneous adenoid cystic carcinoma (CACC) is an extremely rare neoplasm of head and neck region, and is characterized by propensity for local recurrence and perineural invasion. Late distant metastases occur usually to lungs. Although patients with lung metastases from CACC cannot be cured, long-term survival may be possible due to its slow-growing malignancy. We report a case of a 69-year-old female with lung metastases from CACC 23 years after initial surgery of scalp nodule.
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BACKGROUND: Cigarette smoking remains a significant public health problem. However, current treatment programs have not yet succeeded in sufficiently reducing smoking rates. The study aimed to examine whether patients' recognition of "spirometric-lung-age (SLA)" estimated from spirometry data prompts smoking cessation. METHODS: From December 2010 to September 2011, participating smokers were prospectively enrolled into the standardized smoking cessation program (Visits 1-5 for 12 weeks) and assigned single-blindly to either SLA assessment or control groups. The SLA group was informed of the estimated age of their lungs from spirometry analysis and given an opportunity to recognize the difference from their actual chronological age, whereas the control group was not. The primary calculation of outcome was the smoking quit rate on Visit 5, whereas the secondary end-point was the proportion of patients who remained abstinent 1 year later. RESULTS: One hundred and twenty-six Japanese smokers (88 males) participated and were randomly assigned to the SLA group (n=52) or the control group (n=74). The smoking quit rate on Visit 5 was similar in the SLA assessment group and control group (59.6% vs. 41.9%; P=0.0700). However, the proportion of patients who remained abstinent 1 year later was similar in both groups (78.6% vs. 69.0%; P=0.5497). Multivariate logistic regression analysis after adjusting baseline characteristics demonstrated that telling patients their SLA, the use of varenicline, and age were significantly associated with smoking quit rate on Visit 5 whereas only age was associated with remaining abstinent 1 year later. CONCLUSIONS: Telling patients their SLA can become a useful tool prompting smoking cessation among Japanese smokers although other factors such as pharmacotherapy and age also influence the cessation of smoking.
Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/pathology , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Meningeal Neoplasms/drug therapy , Mutation , Female , Humans , Meningeal Neoplasms/secondary , Middle AgedABSTRACT
Bronchial-pulmonary arterial fistula (BPAF) is a rare vascular malformation complicated with racemose hemangioma. We report a case of a 65-year-old male with BPAF with primary racemose hemangioma. Bronchial arteriography demonstrated convolution, dilation, and aneurysm connected with pulmonary artery, suggesting the presence of BPAF, in the left upper lobe. Since a 20-mm sized aneurysm of bronchial artery and BPAF coexisted, he underwent ligation of bronchial arterial aneurysm and left upper lobectomy to prevent hemoptysis. As neither history of prior illness nor histopathologic findings of vascular inflammation was seen, the present case demonstrated BPAF with primary racemose hemangioma. Establishment of non-invasive treatment strategy for BPAF is urgently required.
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PURPOSE: Recent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD-PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH. METHODS: We analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5 mm(2) (%CSA <5) in many CT slices from each of four COPD-PH patients before and after the initiation of pulmonary vasodilator. To evaluate those generalized data from patients with COPD, we evaluated multiple slices from 42 patients whose PH was not clinically suspicious. We also selected five PH patients with idiopathic interstitial pneumonia (IIP-PH) and analyzed serial changes of pulmonary artery enlargement (PA:A ratio). RESULTS: In 42 COPD patients without PH, LAA% had a statistically significant negative correlation with %CSA <5. However, three of four COPD-PH patients manifested no such correlation. In two patients, clinical findings were dramatically improved after the initiation of pulmonary vasodilator. Notably, LAA% and %CSA <5 in those patients correlated significantly after its treatment. In COPD-PH, the PA:A ratio was significantly decreased after the initiation of pulmonary vasodilator therapy (1.25 ± 0.13 vs. 1.13 ± 0.11, p = 0.019), but not in IIP-PH. CONCLUSIONS: Our study demonstrates that the use of quantitative CT analysis is a plausible and beneficial tool for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.
Subject(s)
Hypertension, Pulmonary/diagnostic imaging , Pulmonary Artery/diagnostic imaging , Pulmonary Disease, Chronic Obstructive/diagnostic imaging , Pulmonary Fibrosis/diagnostic imaging , Aged , Bosentan , Endothelin Receptor Antagonists/therapeutic use , Exercise Test , Female , Forced Expiratory Volume , Humans , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/physiopathology , Male , Middle Aged , Pulmonary Artery/physiopathology , Pulmonary Diffusing Capacity , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/physiopathology , Sildenafil Citrate/therapeutic use , Sulfonamides/therapeutic use , Tadalafil/therapeutic use , Tomography, X-Ray Computed , Vasodilator Agents/therapeutic use , Vital CapacityABSTRACT
Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser(1177) and p-Akt at Ser(473) expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system.
Subject(s)
Antihypertensive Agents/pharmacology , Erythropoietin/biosynthesis , Genistein/pharmacology , Hypertension, Pulmonary/drug therapy , Nitric Oxide/physiology , Animals , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Cell Hypoxia , Cyclic GMP/metabolism , Drug Evaluation, Preclinical , Erythropoietin/physiology , Genistein/therapeutic use , Hep G2 Cells , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/physiology , Humans , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/prevention & control , Male , Nitric Oxide Synthase Type III/metabolism , Phosphorylation , Protein Processing, Post-Translational , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction , Vasodilator Agents/pharmacology , Ventricular PressureABSTRACT
A 30-year-old Japanese woman with lymphangioleiomyomatosis (LAM) developed a left chylothorax and chylous ascites. A pleuro-peritoneal communication was confirmed by a scintigram with (99)mTc-labeled macroaggregated-albumin injected into the peritoneal cavity. Video-assisted thoracic surgery revealed a protruding papillary lesion on the left diaphragm. Chyle was oozing into the pleural cavity through this lesion. Histopathological analyses demonstrated that the protrusion was a diaphragmatic LAM lesion and that LAM-associated lymphangiogenesis enabled communication between the pleural and peritoneal cavities through lymphatic vessels. This case demonstrated a new mechanism for chylous pleural effusion in LAM and illustrates the significance of LAM-associated lymphangiogenesis.
Subject(s)
Diaphragm , Lymphangioleiomyomatosis/complications , Muscle Neoplasms/complications , Peritoneal Cavity/physiopathology , Pleural Cavity/physiopathology , Adult , Chylothorax/etiology , Chylous Ascites/etiology , Female , Humans , Lymphangioleiomyomatosis/surgery , Lymphatic Vessels/diagnostic imaging , Lymphatic Vessels/physiopathology , Muscle Neoplasms/surgery , Peritoneal Cavity/diagnostic imaging , Pleural Cavity/diagnostic imaging , Radionuclide ImagingABSTRACT
Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by fibrocellular intimal proliferation and thrombus formation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. Osteopontin (OPN) is a multifunctional cytokine and adhesive protein, and has been demonstrated to be implicated in fibrosis, neointima formation, arterial occlusion by thrombus, and tumor metastases in cooperation with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Herein is described an autopsy case of gastric adenocarcinoma with severe pulmonary hypertension due to PTTM. Histologically, tumor cell emboli markedly induced both fibromuscular intimal thickening and thrombosis, resulting in luminal stenosis and occlusion of small pulmonary arteries and arterioles. Tumor cells, both in the PTTM lesions and primary gastric carcinoma, had positive immunoreactivity for OPN, PDGF, and VEGF. In addition, proliferating fibromuscular intimal cells also showed expression of OPN, PDGF, and VEGF. These findings suggest that OPN may be involved in fibrocellular intimal proliferation and thrombus formation in PTTM together with PDGF and VEGF. To the best of the authors' knowledge this is the first report to demonstrate the possible involvement of OPN in PTTM. It is postulated that OPN is one of the candidate molecules for the development of PTTM.