Human alveolar capillaries undergo angiogenesis in pulmonary veno-occlusive disease

Schraufnagel, Dean E.; Sekosan, Marin; McGee, Thomas P.; Thakkar, Maitreya

doi:10.1183/09031936.96.09020346

Cited by 44 publications

(32 citation statements)

References 21 publications

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“…These abnormalities may be explained by interstitial oedema and/or pulmonary capillary angiogenesis secondary to chronic pulmonary venous obstruction [37]. Interstitial lung disease may indeed be identified in PVOD [12].…”

Section: Discussionmentioning

confidence: 99%

Occult alveolar haemorrhage in pulmonary veno-occlusive disease

Rabiller¹

2006

European Respiratory Journal

131

111

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Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary arterial hypertension that affects predominantly post-capillary pulmonary vessels. A major concern with PVOD is the poor response to available therapies and the risk of pulmonary oedema with continuous intravenous epoprostenol.The present authors hypothesised that alveolar haemorrhage may be a characteristic feature of pulmonary veno-occlusive disease, as compared with other forms of pulmonary arterial hypertension that predominantly involve pre-capillary pulmonary arteries.This paper reports a series of 19 patients with either PVOD (n58) or idiopathic pulmonary arterial hypertension (IPAH; n511) who underwent bronchoalveolar lavage. Cytological analyses were performed and differential counts were made on Perls-stained preparations. The Golde score was used to assess alveolar haemorrhage. As compared with IPAH, PVOD was characterised by a higher percentage of haemosiderin-laden macrophages (40¡37 versus 3¡6%), resulting in elevated Golde scores (81¡88 versus 4¡10).It was concluded that occult alveolar haemorrhage is a common feature of pulmonary venoocclusive disease. Detecting occult alveolar haemorrhage may be of interest in the diagnostic approach of pulmonary veno-occlusive disease.

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Section: Discussionmentioning

confidence: 99%

Occult alveolar haemorrhage in pulmonary veno-occlusive disease

Rabiller¹

2006

European Respiratory Journal

131

111

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“…Extensive capillary damage and venous occlusion were observed, resulting in excessive new capillary formation, sometimes in angiomatoid configurations, and hypertrophy of pulmonary veins and arteries. 33 At the molecular level, it has been suggested that MMCinduced pulmonary vascular dysfunction may be related to its bifunctional alkylating property. Cultured pulmonary-artery endothelial cells exposed to MMC showed similar growth arrest and morphological alterations to monocrotaline pyrrole, another bifunctional alkylating substance known to be a potent trigger for experimental PH in rats.…”

Section: Discussionmentioning

confidence: 99%

Mitomycin-Induced Pulmonary Veno-Occlusive Disease

et al. 2015

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P ulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension (PH). PVOD is characterized by widespread fibrous intimal proliferation of septal veins and preseptal venules, and is frequently associated with pulmonary capillary dilatation and proliferation. 1Although the pathology firmly confirms PVOD, a noninvasive diagnostic approach is usually favored in these fragile patients in whom a lung biopsy carries a high risk of lifethreatening complications. Decreased diffusing capacity of the lung for carbon monoxide, severe hypoxemia, radiological abnormalities on high-resolution computed tomography (CT) scans of the chest, and the occurrence of pulmonary edema after starting pulmonary vasodilator therapy strongly argue for PVOD.1,2 PVOD is a difficult form of PH to diagnose; it is frequently misclassified as idiopathic pulmonary arterial hypertension (PAH). Thus, the true incidence of PVOD is not known precisely, but is considered to represent 10% of cases of PAH 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. Key Words: alkylating agents ◼ antineoplastic agents ◼ complications ◼ drug-related side effects and adverse reactions ◼ GCN2 ◼ hypertension, pulmonary ◼ pulmonary veno-occlusive disease Conclusions-MMC

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“…24 Schraufnagel has also suggested there is new vessel formation in the lungs of a patient with pulmonary venoocclusive disease. 25 At least some metastatic tumors in the lung receive their blood supply either exclusively or predominately from the pulmonary circulation, again suggesting the ability of the pulmonary circulation to undergo an angiogenic response. 26 In further support of the idea that pulmonary angiogenesis may occur in response to chronic hypoxia is the recent report from Pascaud et al, who found that angiostatin, an inhibitor of angiogenesis, aggravated pulmonary hypertension in the hypoxic lung.…”

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Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Stenmark

McMurtry

2005

Circulation Research

118

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C hronic or sustained pulmonary hypertension is a complication of residence at high altitudes and chronic lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, and sleep apnea. Alveolar hypoxia is an important (though probably not exclusive) contributor to the pulmonary hypertension observed in these conditions. Further, it is widely accepted that secondary hypoxic pulmonary hypertension is strongly associated with increased morbidity and reduced survival. 1,2 These facts have led to intense research efforts to identify the underlying mechanisms contributing to this condition, with the ultimate goal of identifying and developing novel therapeutic interventions. This work has relied heavily on the use of animal models, and one of the most commonly used is exposure of rats to chronic-hypoxic conditions by nitrogen dilution or hypobaria. Observations, predominately in this model, have led to the longstanding and widely accepted theory that chronic hypoxic pulmonary hypertension results from a combination of sustained vasoconstriction and vascular remodeling. It is generally believed that the contribution of vasoconstriction is greatest early in the disease process and that structural remodeling of the pulmonary vascular bed becomes progressively more important over time. That structural change is an important determinant of increased resistance and pressure in chronic pulmonary hypertension is supported by observations that over time of exposure to hypoxia, acute reexposure to normal or even high levels of inspired oxygen becomes progressively less effective in reducing the pulmonary arterial pressure. This lack of responsiveness to oxygen, or even to other pulmonary vasodilators such as Ca 2ϩ channel blockers, has led to the concept that chronic hypoxic pulmonary hypertension is associated with a "fixed" structural component responsible for the increased pulmonary vascular resistance. The structural changes thought to contribute to the increased vascular resistance have been broadly characterized into 2 processes: (1) inward remodeling of the pulmonary artery wall and (2) a reduction in the total number of small peripheral pulmonary arteries (a process referred to as rarefaction or pruning of the pulmonary vasculature).The work presented by Hyvel et al challenges, at least in certain ways, both of these concepts. 3 Pulmonary vascular remodeling refers to a process that causes thickening of the arterial wall and is thought to increase resistance by physical encroachment of the lumen of small peripheral pulmonary arteries and arterioles. Because intimal thickening is not usually observed in hypoxic pulmonary hypertension, this reduction in luminal area is believed to be attributable largely to constrictive medial and adventitial thickening. However, using different lung preparation techniques than have been used in most other hypoxic studies (ie, the pulmonary vasculature was "maximally" vasodilated by perfusion with calcium-free plus EGTA physiological saline solution...

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Human alveolar capillaries undergo angiogenesis in pulmonary veno-occlusive disease

Cited by 44 publications

References 21 publications

Occult alveolar haemorrhage in pulmonary veno-occlusive disease

Occult alveolar haemorrhage in pulmonary veno-occlusive disease

Mitomycin-Induced Pulmonary Veno-Occlusive Disease

Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

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