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.

The discovery of complex vascular lesions in SHIV-nef- but not SIV-infected animals, and the presence of Nef in the vascular cells of patients with HRPH, suggest that Nef plays a key role in the development of severe pulmonary arterial disease.

Using a HeLa cell line stably transfected with the tat gene from human immunodeficiency virus type 1, we have found that the expression of the regulatory Tat protein suppresses the expression ofcellular Mn-containing superoxide dismutase (Mn-SOD). This enzyme is one of the cell's primary defenses against oxygen-derived free radicals and is vital for maintaining a healthy balance between oxidants and antioxidants. The parental HeLa cells expressed nearly equivalent amounts of Cu,Zn-and Mn-SOD isozymes. Those cels expressing the Tat protein, however, contained 52% less Mn-SOD activity than parental cells, whereas that of the Cu,Zn enzyme was essentially unchanged. The steady-state levels of Mn-SOD-specific RNAs were also lower in the HeLa-tatcell line than in the parental line. No difference was seen in the steady-state levels of Cu,Zn-SOD-specific RNAs. In addition to the decreased Mn-SOD activity, HeLa-tatceDls showed evidence of increased oxidative stress. Carbonyl proteins were markedly higher, and total cellular sulfhydryl content decreased in ceDl extracts at a faster rate, probably reflecting ongoing lipid peroxidation. HeLa and HeLa-tat extracts were incubated with radiolabeled Mn-SOD transcripts, and the reaction products were subjected to UV crosslinking, digestion with ribonuclease A, and electrophoretic analysis. The results suggest a direct interaction between Tat protein and Mn-SOD gene transcripts.

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