Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a critical mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the VEGF receptors in both rats and mice. Emphysema was reproduced with intra-tracheal instillation of ceramide in naïve mice. A feed-forward mechanism of ceramide synthesis due secretory acid sphingomyelinase was supported by the neutralizing effects of ceramide-specific antibody in mice and by sphingomyelinase-deficient fibroblasts. Stimulation of sphingosine-1-phosphate signaling prevented lung apoptosis, implicating that ceramide to sphingosine-1-phosphate balance is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in patients with smoking-induced emphysema position ceramide upregulation as a critical pathogenetic element and a promising target in this disease lacking effective therapies.

The secondary role of pathology in the present clinical management of pulmonary hypertension (PH) reflects to some extent the limitations of the current understanding of the disease. Ample room exists for the diagnostic translation of the pathobiologic studies, with the goal of improving the diagnostic and prognostic power of the pathologic assessment of pulmonary vascular remodeling. This article seeks to show the complementarities of the pathology and pathobiology of PH.

Rtp801, a stress – related protein triggered by adverse environmental conditions, inhibits mTOR and enhances oxidative stress – dependent cell death. We postulated that Rtp801 acts as potential amplifying switch in the development of cigarette smoke – induced lung injury, leading to emphysema. Rtp801 was overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The upregulation of Rtp801 expression by cigarette smoke in the lung relied on oxidative stress – dependent activation of the CCAAT response element. Rtp801 was necessary and sufficient for NF – κ B activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF – kB activation, alveolar inflammation, oxidative stress, and apoptosis of alveolar septal cells. On the other hand, Rtp801 − / − mice were markedly protected against acute cigarette smoke – induced lung injury, partly via increased mTOR signaling, and, when exposed chronically, against emphysema. Our data support the notion that Rtp801 may represent an important molecular sensor and mediator of lung injury to cigarette smoke.

Severe pulmonary hypertension is irreversible and often fatal. Abnormal proliferation and resistance to apoptosis of endothelial cells (ECs) and hypertrophy of smooth muscle cells in this disease are linked to decreased mitochondria and preferential energy generation by glycolysis. We hypothesized this metabolic shift of pulmonary hypertensive ECs is due to greater hypoxia inducible-factor1␣ (HIF-1␣) expression caused by low levels of nitric oxide combined with low superoxide dismutase activity. We show that cultured ECs from patients with idiopathic pulmonary arterial hypertension (IPAH-ECs) have greater HIF-1␣ expression and transcriptional activity than controls under normoxia or hypoxia , and pulmonary arteries from affected patients have increased expression of HIF-1␣ and its target carbonic anhydrase IX. Severe pulmonary arterial hypertension is characterized by significant increases in pulmonary artery pressures to levels present in the systemic circulation. Pulmonary hypertension (PH) is a major determinant of morbidity and mortality in several pulmonary and heart diseases. The pathogenesis of severe pulmonary arterial hypertension has revolved around excessive vasoconstriction and/or abnormal pulmonary vascular remodeling. Recent experimental evidence has linked the pulmonary vascular disease in severe pulmonary arterial hypertension to an abnormal proliferative vascular cell phenotype, which is also characterized by resistance to endothelial and/or vascular smooth muscle cell apoptosis.

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Mutations in transforming growth factor-beta family receptor-II, bone morphogenetic protein receptor-2, and activin-like kinase-1 have been associated with pulmonary hypertension. In the present study, we determined that pulmonary arteries in normal lungs and in lungs of patients with emphysema and idiopathic pulmonary arterial hypertension comparably expressed transforming growth factor-beta receptors I and II, Smad(1, 5, 8), Smad2, Smad3, Smad4, phosphorylated Smad(1, 5, 8), and phosphorylated Smad2 (the latter two both indicative of active in vivo signaling) in endothelial cells, as assessed by immunohistochemistry and quantitative morphometry. Medial or intimal smooth muscle cells had weak or absent expression of these molecules. In clear contrast to endothelial cell expression in pulmonary arteries and in endothelial cells lining incipient vessels within plexiform lesions of hypertensive lungs, endothelial cells present in the core of the lesions lacked expression of all examined members of the signaling molecules. These findings were made irrespective of the mutation status of bone morphogenetic protein receptor-2 in hypertensive patients. Our findings suggest that pulmonary artery endothelial cells in both normal and severely hypertensive lungs have active transforming growth factor-beta family signaling, and that loss of signaling might contribute to the abnormal growth of endothelial cells in plexiform lesions in idiopathic pulmonary arterial hypertension.

Berdyshev EV, Lungarella G, Tuder RM. Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide.

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