Broilers are susceptible to pulmonary hypertension syndrome (PHS; ascites syndrome) when their pulmonary vascular capacity is anatomically or functionally inadequate to accommodate the requisite cardiac output without an excessive elevation in pulmonary arterial pressure. The consequences of an inadequate pulmonary vascular capacity have been demonstrated experimentally and include elevated pulmonary vascular resistance (PVR) attributable to noncompliant, fully engorged vascular channels; sustained pulmonary arterial hypertension (PAH); systemic hypoxemia and hypercapnia; specific right ventricular hypertrophy, and right atrioventricular valve failure (regurgitation), leading to central venous hypertension and hepatic cirrhosis. Pulmonary vascular capacity is broadly defined to encompass anatomical constraints related to the compliance and effective volume of blood vessels, as well as functional limitations related to the tone (degree of constriction) maintained by the primary resistance vessels (arterioles) within the lungs. Surgical occlusion of 1 pulmonary artery halves the anatomical pulmonary vascular capacity, doubles the PVR, triggers PAH, eliminates PHS-susceptible broilers, and reveals PHS-resistant survivors whose lungs are innately capable of handling sustained increases in pulmonary arterial pressure and cardiac output. We currently are using i.v. microparticle injections to increase the PVR and trigger PAH sufficient in magnitude to eliminate PHS-susceptible individuals while allowing PHS-resistant individuals to survive as progenitors of robust broiler lines. The microparticles obstruct pulmonary arterioles and cause local tissues and responding leukocytes to release vasoactive substances, including the vasodilator NO and the highly effective vasoconstrictors thromboxane A(2) and serotonin [5-hydroxytryptamine (5-HT)]. Nitric oxide is the principal vasodilator responsible for modulating (attenuating) the PAH response and ensuing mortality triggered by i.v. microparticle injections, whereas microparticle-induced increases in PVR can be attributed principally to 5-HT. Our observations support the hypothesis that susceptibility to PHS is a consequence of anatomically inadequate pulmonary vascular capacity combined with the functional predominance of the vasoconstrictor 5-HT over the vasodilator NO. The contribution of TxA(2) remains to be determined. Selecting broiler lines for resistance to PHS depends upon improving both anatomical and functional components of pulmonary vascular capacity.

Previous hemodynamic evaluations demonstrated that pulmonary arterial pressure (PAP) is higher in broilers that are susceptible to pulmonary hypertension syndrome (PHS, ascites) than in broilers that are resistant to PHS. We compared key pulmonary hemodynamic parameters in broilers from PHS-susceptible and PHS-resistant lines (selected for 12 generations under hypobaric hypoxia) and in broilers from a relaxed (control) line. In experiment 1 the PAP was measured in male broilers in which a flow probe positioned on one pulmonary artery permitted the determination of cardiac output and pulmonary vascular resistance (PVR). The PAP and relative PVR were higher in susceptible broilers than in relaxed and resistant broilers, whereas absolute and relative cardiac output did not differ between lines. In experiment 2 male and female broilers from the 3 lines were catheterized to measure pressures in the wing vein, right atrium, right ventricle, pulmonary artery, and pulmonary veins (WP, wedge pressure). The transpulmonary pressure gradient (TPG) was calculated as (PAP-WP), with PAP quantifying precapillary pressure and WP approximating postcapillary pulmonary venous pressure. When compared with resistant and relaxed broilers, PAP values in susceptible broilers were > or =10 mmHg higher, TPG values were > or =8 mmHg higher, and WP values were < or =2 mmHg higher, regardless of sex. The combined hemodynamic criteria (elevated PAP and PVR combined with a proportionally elevated TPG) demonstrate that susceptibility to PHS can be attributed primarily to pulmonary arterial hypertension associated with increased precapillary (arteriole) resistance rather than to pulmonary venous hypertension caused by elevated postcapillary (venous and left atrial) resistance.

Plexiform lesions develop in the pulmonary arteries of humans suffering from idiopathic pulmonary arterial hypertension (IPAH). Plexogenic arteriopathy rarely develops in existing animal models of IPAH. In this study, plexiform lesions developed in the lungs of rapidly growing meat-type chickens (broiler chickens) that had been genetically selected for susceptibility to IPAH. Plexiform lesions developed spontaneously in: 42% of females and 40% of males; 35% of right lungs, and 45% of left lungs; and, at 8, 12, 16, 20, 24, and 52 weeks of age the plexiform lesion incidences averaged 52%, 50%, 51%, 40%, 36%, and 22%, respectively. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries exhibiting intimal proliferation. Perivascular mononuclear cell infiltrates consistently surrounded the affected arteries. Proliferating intimal cells fully or partially occluded the arterial lumen adjacent to plexiform lesions. Broilers reared in clean stainless steel cages exhibited a 50% lesion incidence that did not differ from the 64% incidence in flock mates grown on dusty floor litter. Microparticles (30 μm diameter) were injected to determine if physical occlusion and focal inflammation within distal pulmonary arteries might initiate plexiform lesion development. Three months postinjection no plexiform lesions were observed in the vicinity of persisting microparticles. Broiler chickens selected for innate susceptibility to IPAH represent a new animal model for investigating the mechanisms responsible for spontaneous plexogenic arteriopathy.

Two experiments were conducted to evaluate the effects of arginine (Arg) and vitamin E (VE) on ascites (pulmonary hypertension syndrome) parameters, nitric oxide synthase (NOS) activity, and cardiopulmonary performance after an acute challenge with epinephrine (Epi). One-day-old male broilers (n = 100) were fed a commercial corn-soybean meal-based diet meeting NRC (1994) requirements, including 1.2% Arg and 40 IU of VE/kg. In experiment 1, birds were provided tap water (control), water with 0.3% Arg (HArg), water with 400 IU of VE/L (HVE), or a combination of both compounds (Arg-VE). In experiment 2, the treatment groups were similar but the VE was incorporated in the diet (400 IU/ kg of feed). At d 18, temperature was reduced to amplify the incidence of pulmonary hypertension. Body weight and hematocrit were recorded weekly. From d 28 to 42, cardiopulmonary performance was evaluated in clinically healthy, anesthetized birds (n = 7 to 8/treatment). A pulmonary artery and a systemic artery were cannulated, the birds were allowed to stabilize for 10 min (basal), an i.v. injection of Epi was applied (1 or 0.5 mg/kg of BW, experiment 1 and 2, respectively), and a second dose was applied 20 min later. Pulmonary arterial pressure (PAP), mean arterial pressure (MAP), and heart rate (HR) were recorded continuously and data were analyzed by repeated measures ANOVA. The NOS activity was estimated through the conversion of 14C-Arginine to 14C-citrulline in isolated pulmonary arteries. Right/total ventricular weight ratio (RV/TV) was recorded at the end of the experiment. Body weight, RV/TV, and hematocrit values were not significantly affected by the dietary treatments. The PAP increased (P < 0.01) within 30 s after Epi in all treatments, except the HArg treatment in experiment 2. Overall, the time taken for PAP to return to basal levels was longer in the Arg-VE birds and shorter in the HArg birds, particularly after the second challenge. However, although NOS activity was highly variable, birds fed HArg tended to have the lowest NOS activity of all groups. The levels of VE supplementation used in these experiments did not improve cardiopulmonary performance or NOS activity in isolated pulmonary arteries.

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