Abstract 3156: Obstructive Proliferative Vasculopathy in a Rat Model of Hepatopulmonary Syndrome Reflects Activation of Inducible Nitric Oxide Synthase: An Unexpected Histological Finding in Rats With Low Pulmonary Vascular Resistance
Introduction: Many patients with liver cirrhosis develop the hepatopulmonary syndrome (HPS), a syndrome characterized by high cardiac output and hypoxemia due to intrapulmonary shunting. If liver transplant is successful HPS resolves. Common bile duct ligation (CBDL) is an accepted animal model of HPS and is associated with increased nitric oxide production. We hypothesized that pulmonary circulation in rats with HPS would show dilated capillaries and arterio-venous fistulae related to increased activity of inducible nitric oxide synthase (iNOS).
Methods: Adult, male, Sprague-Dawley rats underwent midline laparotomy with either CBDL using a vascular clip or a sham procedure where the clip was placed adjacent to the CBD. Cardiac output was followed weekly using Doppler echocardiography. CBDL rats received either no treatment or an iNOS inhibitor, L-NIL (16 mg/L in drinking water). Four weeks after surgery the rats underwent heart catheterization to assess hemodynamics and were sacrificed. Muscularization of the pulmonary arteries was determined on paraffin-embedded lung sections after staining for von Willebrand’s factor and smooth muscle cell actin. Cell proliferation was assessed using proliferating cell nuclear antigen (PCNA) immunofluorescence.
Results: Cardiac output and CBD diameter increased in parallel each week during 1 month of follow-up. The cardiac output was higher in CBDL versus Sham (150±13 versus 94±15 ml/min P<0.001). There was no difference in filling pressures between CBDL and Sham groups on catheterization. Capillary diameter was increased in CBDL lungs. Surprisingly, % medial thickness of small (20 –50 μm) pulmonary arteries in CBDL animals was increased versus sham animals and this was reduced by L-NIL (32±6, 20±5, vs. 24±7%, respectively P<0.05). The number of PCNA positive cells per high-powered field was higher in CBD versus Sham and was reduced by L-Nil (21.7±4.7, 5.6±3.1 vs. 16.2±5.3 cells, P<0.001).
Conclusion: CBDL increased cardiac output and, despite the absence of pulmonary hypertension, caused an obstructive, proliferative vasculopathy of small pulmonary arteries in part due to iNOS. HPS may be a proliferative vasculopathy, driven partly by iNOS, and paradoxically masked by the iNOS activity.