OBJECTIVEBased on establishment of four rat models of experimental pulmonary hypertension (PH), the authors examined the inhibition of matrix metalloproteinases (MMPs) by doxycycline and its effect on the development of PH and associated pulmonary vascular remodeling.

METHODHealthy male Sprague-Dawley rats (weight 350 g to 400 g) were randomly divided into nine groups: Normal control group (N), four model groups (H, M, P, PM) and their corresponding drug intervention groups (HD, MD, PD, PMD) in which doxycycline was given by gavage at a 20 mg/kg daily dosage. On day 28 (day 35 for PM and PMD models), the animals were catheterized to record mean pulmonary arterial pressure (mPAP) and then sacrificed. Fulton Index [RV/(LV + S)] was measured immediately. Morphometric parameters, including percent vascular wall thickness and muscularization of non-muscularized peripheral pulmonary arterioles were determined microscopically. The activity of MMPs was measured by gelatin zymography in the lung tissue.

RESULTS(1) Rats in all model groups (H, M, P, PM) developed significant pulmonary arterial hypertension and right ventricular hypertrophy in comparison with their corresponding drug intervention groups (HD, MD, PD, PMD) and normal control group (N) (P < 0.01). For example, mPAP (mm Hg)(1 mm Hg = 0.133 kPa):N: 18.10 +/- 1.45, H: 27.20 +/- 1.55, HD: 23.90 +/- 2.13; Fulton Inedx(%):N: 23.41 +/- 1.84, H: 34.44 +/- 2.70, HD: 27.55 +/- 2.45. (2) The percent vascular wall thickness (WT%) and percentage of muscularization of non-muscular pulmonary arterioles were significantly increased in all model groups compared with drug intervention groups and normal group (P < 0.01). For example, WT%:N: 10.90 +/- 3.11, H:41.41 +/- 5.21, HD: 17.73 +/- 3.12; Muscularization(%):N: 13.83 +/- 3.72, H: 44.93 +/- 2.43, HD: 29.89 +/- 4.45. (3) The activity of MMPs was inhibited by doxycycline effectively as assessed by gelatin zymography (P < 0.01). For example, the activity of MMP2 (A x 10(3)):N: 1.43 +/- 0.24, H: 3.58 +/- 0.28, HD: 2.29 +/- 0.31.

CONCLUSIONDoxycycline attenuated PH and associated pulmonary vascular remodeling in all rat PH models. The study suggests that high expression and enhanced activity of MMPs may play a brutial role in the development of PH. Such phenomenon seems to be common in a variety of PH models of different etiology.