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Background-Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. Methods and Results-Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]ϭ42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg Ϫ1 · d Ϫ1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAPϭ36 mm Hg) and 6 weeks (mPAPϭ24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-␣ and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. Conclusions-Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury. (Circulation.

Hypertensive pulmonary vascular disease is characterized by abnor-prostanoids (7), which dilate reactive blood vessels and supmal proliferation of vascular endothelial and smooth muscle cells, press the growth of smooth muscle cells (8). Additional antileading to occlusion of pulmonary arterioles, pulmonary hypertenproliferative strategies for treatment of vascular occlusive sion, right ventricular failure, and death. Compounds with antiprodiseases are warranted (9). liferative effects on vascular endothelial and smooth muscle cells,Our group has previously demonstrated that antiproliferasuch as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductive drugs with no acute vasodilator properties effectively tase inhibitors, may prevent the development of experimental hyattenuate vascular remodeling with neointimal formation, pertensive pulmonary vascular disease. Pneumonectomized rats inpulmonary arterial hypertension, and right ventricular hyperjected with monocrotaline at 7 days develop severe hypertensive trophy in pneumonectomized, monocrotaline-injected rats (10, pulmonary vascular disease with neointimal formation. Rats were 11). The combination of pneumonectomy with monocrotaline randomized to receive either vehicle or treatment with the HMG-CoA reductase inhibitor simvastatin (2 mg/kg per day). By Day injection results in more severe pulmonary arterial hyperten-35, rats that received vehicle had higher mean pulmonary arterial sion (mean pulmonary arterial blood pressure [Ppa] ϭ 45 mm pressures (53 Ϯ 2 mm Hg) and right ventricular hypertrophy (right Hg) (10-12) than monocrotaline alone (Ppa ϭ 32 mm Hg) ventricle/[left ventricle plus septum] [RV/LVϩS] ϭ 0.78 Ϯ 0.09) (13-15). Importantly, only the combination of pneumonecthan rats in Group PMS 5-35 that received simvastatin from Day 5 to tomy with monocrotaline injection produces neointimal for-35 (mean pulmonary arterial pressure ϭ 27 Ϯ 3 mm Hg, RV/LVϩS ϭ mation and vascular obliteration of small pulmonary arteri-0.34 Ϯ 0.08; p р 0.001). Pulmonary vascular remodeling with neointioles that reproduces many of the pathological features of mal formation consisting of vascular smooth muscle cells was more human PPH (2, 9). severe in vehicle-treated rats (vascular occlusion score, 1.98 Ϯ 0.02) It is increasingly recognized that treatment with 3-hydroxthan in Group PMS 5-35 (vascular occlusion score, 0.59 Ϯ 0.46; p Ͻ ymethyl-3-methylglutaryl-coenzyme A (HMG-CoA) reduc-0.001). In addition, lung endothelial nitric oxide synthase gene expression was decreased in vehicle-treated animals but was re-tase inhibitors, statins, produces improvements in cardiovasstored toward normal levels in simvastatin-treated animals. Simcular outcomes that are incompletely explained by reductions vastatin attenuates monocrotaline-induced pulmonary vascular in cholesterol (16, 17). Statins exert direct antiinflammatory remodeling with neointimal formation, pulmonary arterial hyperand antiproliferative effects on the components of vascular tension, and right ventricular hypertrophy in rats...

Across several geographical settings, sarcoidosis and infections are the most common causes of pulmonary granulomas diagnosed in pathological specimens. Fungi are more commonly identified than mycobacteria in the USA, whereas the reverse is true in other countries. A definite aetiology cannot be demonstrated in more than a third of all cases of pulmonary granulomas, even after histological examination. These findings highlight the need to submit material for histology as well as cultures in all cases in which granulomatous disease enters the differential diagnosis.

The acute respiratory distress syndrome (ARDS) has been recognized for more than three decades as a cause of respiratory failure in patients with a variety of illnesses. Clinically, it is characterized by pulmonary edema, refractory hypoxemia, diffuse pulmonary infiltrates, and altered lung compliance. Pathologically, it is distinguished by infiltration of the lungs with inflammatory cells, interstitial and alveolar edema, hyaline membrane formation, and ultimately fibrosis. Although we have learned much about the pathophysiology of this inflammatory syndrome since its earliest descriptions, ARDS continues to claim the lives of 40%-70% of its victims. Many treatment strategies have been used to prevent or treat ARDS, but thus far the most encouraging strategy to prevent lung injury and improve survival is mechanical ventilation with low tidal volumes and high levels of positive end-expiratory pressure.

Triptolide (PG490, 97% pure) is a diterpenoid triepoxide with potent anti-inflammatory and immunosuppressive effects in transformed human bronchial epithelial cells and T cells (Qiu D, Zhao G, Aoki Y, Shi L, Uyei A, Nazarian S, Ng JC-H, and Kao PN. J Biol Chem 274: 13443-13450, 1999). Triptolide, with an IC(50) of approximately 20-50 ng/ml, inhibits normal and transformed human bronchial epithelial cell expression of interleukin (IL)-6 and IL-8 stimulated by phorbol 12-myristate 13-acetate (PMA), tumor necrosis factor-alpha, or IL-1 beta. Nuclear runoff and luciferase reporter gene assays demonstrate that triptolide inhibits IL-8 transcription. Triptolide also inhibits the transcriptional activation, but not the DNA binding, of nuclear factor-kappa B. A cDNA array and clustering algorithm analysis reveals that triptolide inhibits expression of the PMA-induced genes tumor necrosis factor-alpha, IL-8, macrophage inflammatory protein-2 alpha, intercellular adhesion molecule-1, integrin beta(6), vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, GATA-3, fra-1, and NF45. Triptolide also inhibits constitutively expressed cell cycle regulators and survival genes cyclins D1, B1, and A1, cdc-25, bcl-x, and c-jun. Thus anti-inflammatory, antiproliferative, and proapoptotic properties of triptolide are associated with inhibition of nuclear factor-kappa B signaling and inhibition of genes known to regulate cell cycle progression and survival.

Convalescence is prolonged, regardless of whether the patient receives treatment.

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