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Background: As a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats., Methods: PVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg - 1 ·wk - 1 for 2 weeks. Inhalation of hydrogen gas (H 2 ) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined., Results: Inhaled H 2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H 2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H 2 preserved p-Smad3 and induced p-Smad1/5/9., Conclusion: Inhalation of H 2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H 2 ., (© 2024. The Author(s).)

Background: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported., Research Question: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?, Study Design and Methods: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum)., Results: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m 2 ), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively., Interpretation: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.

Trichloroethylene (TCE) is a chlorinated solvent that has been used widely around the world in the twentieth century for metal degreasing and dry cleaning. Although TCE displays general toxicity and is classified as a human carcinogen, the association between TCE exposure and respiratory disorders are conflicting. In this review we aimed to systematically evaluate the current evidence for the respiratory effects of TCE exposure and the implications for the practicing clinician. There is limited evidence of an increased risk of lung cancer associated with TCE exposure based on animal and human data. However, the effect of other chlorinated solvents and mixed solvent exposure should be further investigated. Limited data are available to support an association between TCE exposure and respiratory tract disorders such as asthma, chronic bronchitis, or rhinitis. The most consistent data is the association of TCE with autoimmune and vascular diseases such as systemic sclerosis and pulmonary veno-occlusive disease. Although recent data are reassuring regarding the absence of an increased lung cancer risk with TCE exposure, clinicians should be aware of other potential respiratory effects of TCE. In particular, occupational exposure to TCE has been linked to less common conditions such as systemic sclerosis and pulmonary veno-occlusive disease., (Copyright © 2017. Published by Elsevier Ltd.)

Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 μg of i.p. TDM in light mineral oil (TDM-IP). At day 7, another injection of 10 μg of i.v. TDM in oil/water emulsion was given (TDM-IV). The i.p./i.v. TDM (TDM-IVIP) group was compared with mice injected once with i.v. or i.p. TDM. The responses to TDM-IP, TDM-IV, or TDM-IPIV were consistent between mouse strains. Mice that received TDM-IV and TDM-IPIV had inflammatory pathologic findings with increases in inflammatory and T-cell cytokines, and the TDM-IPIV group had further enhancement of IL-10 and granulocyte-macrophage colony-stimulating factor. The TDM-IPIV group had increased CD4(+) T cells in lung tissue, significantly increased coagulation, decreased clot formation time, and increased maximum clot firmness. Masson's trichrome staining revealed increased deposition of collagen in the occluded vasculature. TDM-IPIV promotes a hypercoagulopathy state, independent of inflammation. This new model argues that TDM is sufficient to generate the hypercoagulopathy observed in patients with TB., (Copyright © 2016. Published by Elsevier Inc.)

Background: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD., Methods and Results: We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats., Conclusions: MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease., (© 2015 American Heart Association, Inc.)

5-Ethynyl-2'-deoxyuridine (EdU) incorporation is becoming the gold standard method for in vitro and in vivo visualization of proliferating cells. The small size of the fluorescent azides used for detection results in a high degree of specimen penetration. It can be used to easily detect DNA replication in large tissue samples or organ explants with low proliferation and turnover of cells formerly believed to be in a "terminal" state of differentiation. Here we describe a protocol for the localization and identification of proliferating cells in quiescent or injured pulmonary vasculature, in a model of pulmonary veno-occlusive disease (PVOD). PVOD is an uncommon form of pulmonary hypertension characterized by progressive obstruction of small pulmonary veins. We previously reported that mitomycin-C (MMC) therapy is associated with PVOD in human. We demonstrated that MMC can induce PVOD in rats, which currently represents the sole animal model that recapitulates human PVOD lesions. Using the EdU assay, we demonstrated that MMC-exposed lungs displayed areas of exuberant microvascular endothelial cell proliferation which mimics pulmonary capillary hemangiomatosis, one of the pathologic hallmarks of human PVOD. In vivo pulmonary cell proliferation measurement represents an interesting methodology to investigate the potential efficacy of therapies aimed at normalizing pathologic angioproliferation.

Pulmonary venoocclusive disease (PVOD) is a rare cause of pulmonary hypertension characterized by a progressive clinical course and poor outcomes if not treated by early lung transplantation. The pathogenesis of PVOD remains poorly understood. We report PVOD that developed in 2 young women soon after the initiation of oral contraceptives (OCs). The first patient is a 14-year-old girl, with no medical history, who started taking an OC 3 weeks before the onset of symptoms. The second patient is an 18-year-old girl, diagnosed 2 years previously with systemic lupus erythematosus and lupus anticoagulant, who started taking an OC 4 months before the onset of symptoms. Both patients required lung transplantation. Radiographic and histopathologic findings in both patients showed features of PVOD. Only 1 prior patient with PVOD and a handful of unclassified patients with pulmonary hypertension in association with OCs have been documented. The importance of PVOD as the basis of pulmonary hypertension in patients with connective tissue disease has been recently proposed, as well as the role of thrombogenesis, in the development of PVOD. The temporal sequence in these 2 patients suggests the thrombogenic action of OCs may contribute to the development of PVOD, with or without underlying connective tissue disease., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary veno-occlusive disease (PVOD), an uncommon cause of pulmonary hypertension (PH) has been reported following treatment of a variety of different malignancies with various chemotherapy. We report here the cases of two patients with non-small cell lung cancer (NSCLC) who developed fatal PH after combined treatment with surgery and a mitomycin containing perioperative chemotherapy (PCT). PVOD was documented at autopsy in one patient and was strongly suspected in the other patient who had an identical clinical presentation and in whom the work-up looking for another cause of PH was negative. Mitomycin was incriminated in both cases. Without questioning the potential interest of perioperative chemotherapy in resectable NSCLC, these observations illustrate the risks related to the combination of pneumotoxic chemotherapy and thoracic surgery.

A multicentre phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with refractory or relapsed indolent non-Hodgkin's lymphoma. Thirty-six patients were enrolled onto the study, including 11 cases of mantle cell lymphoma (MCL), 10 cases of chronic lymphocytic leukaemia (CLL)/lymphocytic lymphoma, nine cases of follicular lymphoma, four cases of lymphoplasmacytic lymphoma and two cases of T-cell lymphoma. Gemcitabine 1 g/m(2) was administered as a 30-min infusion on d 1, 8 and 15 of a 28-d schedule, up to a maximum of six cycles. Complete responses were observed in two patients with MCL, and partial responses were observed in seven patients, including three patients with CLL/lymphocytic lymphoma, two patients with T-cell lymphoma, one patient with MCL and one patient with follicular lymphoma. Minor responses were observed in three patients, including two patients with MCL and one patient with CLL. The median duration of response was 150 d and the overall progression-free survival was 342 d. Haematological toxicity was observed as grade 3-4 leucopenia in 12 patients (33%) and grade 3-4 thrombocytopenia in 18 patients (50%). Severe non-haematological toxicity included one case of fatal veno-occlusive disease, one case of thrombotic microangiopathy leading to terminal renal failure, one case of capillary leak syndrome, one case of myocardial infarction and drug-induced fever in two patients. These data suggest that gemcitabine displays activity in patients with MCL and CLL/lymphocytic lymphoma. Haematological toxicity was frequent in these heavily treated patients. Severe non-haematological toxicity was significant and should be taken into account in the design of future trials.

Pulmonary thrombosis in the course of shock remains life-threatening, despite advances in diagnosis, prophylaxis and therapy of the disease. Tumour necrosis factor-alpha (TNF-alpha) is an important mediator of shock. The aim of this study was to analyze the morphological changes in the pulmonary capillary bed in rats after intraperitoneal administration of multiple doses of TNF-alpha (10 microg TNF-alpha/24 h for 5 days; biological activity of 2-4x10(7)U/mg of protein). Morphological investigations were undertaken by light and transmission electron microscopy with emphasis on pulmonary thrombopoiesis. The study confirmed that the lungs may be an important site of extramedullary thrombopoiesis in the course of shock. The observations also suggested that megakaryocytes shed large fragments of cytoplasm within the pulmonary capillary bed and that megakaryocytes with copious cytoplasm occlude pulmonary vessels., (Copyright 1999 W.B. Saunders Company Ltd.)

A 67-old man was referred to our hospital because of dyspnea on exertion and severe hypoxia. He had been given, tegafur and OK 432 for seven years following an operation for gastric cancer. Pulmonary hypertension was noted by right heart catheterization. The findings of a transbronchial lung biopsy resulted in a diagnosis of pulmonary veno-occlusive disease. Pulmonary hemodynamic studies were performed for five different agents: nifedipine, beroprast sodium (PGI2), nitroglycerin, theophylline, and isosorbide dinitrate. However, none of these agents showed significant effects on pulmonary arterial pressure or pulmonary vascular resistance. Treatment with glucocorticoid relieved the patient's symptoms without any apparent effect on pulmonary hemodynamics. The long-term administration of anticancerous agents (tegafur) were thought to have caused pulmonary veno-occlusive disease to develop in this patient.

It is apparent that a variety of vascular disorders have been reported after the administration of antineoplastic agents. However, it is not clear whether all of these entities are related to cytotoxic drugs, the malignancy itself, or some other unrelated factor. Nonetheless, there does appear to be a cause-effect relationship between cisplatin, bleomycin, velban chemotherapy, and Raynaud's phenomenon. In addition, painful acral erythema may occur in association with several drugs, especially protracted infusions of 5-fluorouracil and high-dose cytosine arabinoside. Mitomycin is the most common cause of the thrombotic microangiopathic syndrome, and in the majority of cases it is a lethal event. Unfortunately, HVOD is a major toxic effect of many preparatory bone marrow transplantation protocols and ways to prevent this potentially life-threatening complication should be avidly pursued. In this regard, pentoxifylline and low-dose heparin have recently been reported to be effective in preventing HVOD. Although recent reports have documented thromboses and thromboembolic events in patients with breast cancer treated with cytoxan, methotrexate, and 5-fluorouracil-based protocols, only one study had a no-treatment control arm. Future breast cancer studies should evaluate this problem prospectively. More studies are needed to help elucidate the pathogenesis of vascular toxicity associated with chemotherapy.

We report three cases of pulmonary veno-occlusive disease which developed following treatment for malignant neoplasms. Two patients received single agent BCNU chemotherapy for malignant gliomas. The third patient underwent combination radiation and chemotherapy for Hodgkin's disease. Isolated case reports of pulmonary veno-occlusive disease following therapy for malignant disease are reviewed and clinical features summarized. Pulmonary veno-occlusive disease in this setting is thought to be rare. However, the diagnosis is rarely suspected clinically and is difficult to diagnose pathologically. Therefore, the true incidence of this complication is unknown and may be higher than believed. It is important that both clinician and pathologist be aware of this entity; otherwise, elastic tissue stains may not be performed and the diagnosis missed.