PULMONARY-HYPERTENSION IN A MURINE MODEL OF THE ACQUIRED-IMMUNODEFICIENCY-SYNDROME

Rapidly accumulating evidence suggests that a proportion of patients with acquired immunodeficiency syndrome (AIDS) develop hypertensive pulmonary vascular disease reminiscent of primary pulmonary hypertension. As an initial step to explore the link between AIDS and hypertensive pulmonary vascular disease, the present study determined whether pulmonary hypertension is present in a well-characterized murine model of retrovirus-induced immunodeficiency. In agreement with previous reports, mice infected with the LP-BM5 murine leukemia virus developed polyclonal B and T cell activation followed by progressive and severe B and T cell immunodeficiency. At 12 wk postinfection, when persistent immunodeficiency was established, mice were anesthetized, and right ventricular systolic pressure was determined in open-chest, mechanically ventilated animals. Mean right ventricular systolic pressure was 14.7 +/- 1.3 mm Hg in control animals and was increased significantly to 22.5 +/- 3.2 mm Hg in virus-infected mice. Right ventricular hypertrophy was also present in infected mice as evidenced by a 27% increase in the ratio of right to left ventricular weights; there were no group-dependent differences in the left ventricular to total-body weight ratio. Morphometric evaluation indicated that medial thickness in muscularized pulmonary arteries, expressed as a percentage of the external diameter, was 9.6 +/- 0.4% in control lungs and increased to 14.4 +/- 0.5% in lungs from infected animals. Qualitative histopathologic analysis suggested increased perivascular collagen deposition in lungs from infected animals relative to control animals. Unlike AIDS patients with pulmonary hypertension, infected mice did not exhibit plexiform lesions or intimal fibrosis of the pulmonary arteries. Neither hematocrits nor arterial PO2 values differed between control and infected mice, indicating that chronic hypoxia did not contribute to the pulmonary hypertensive response to the virus. Compared with controls, lungs from infected mice contained fourfold more lymphocytes, consisting primarily of CD4(+) T cells and B cells. Nearly 35% of the CD4(+) T cells were activated in virus-infected mice, whereas only 15% of this lymphocyte population was activated in control mice. These findings suggest that a murine model of AIDS exhibits pulmonary hypertension that cannot be attributed to chronic hypoxia and that is associated with substantial increases in the pulmonary immune cell population. This murine model maybe useful for delineating pathogenic mechanisms underlying pulmonary hypertension in the setting of AIDS.