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.
The pulmonary hypertensive response to pulmonary vascular obstruction caused by intravenously injected microparticles is amplified by pretreatment with N(omega)nitro-L-arginine methyl ester (L-NAME). The L-NAME prevents the synthesis of the potent vasodilator nitric oxide (NO) by inhibiting both the constitutive [endothelial NO synthase (eNOS or NOS-3)] and inducible [inducible NO synthase (iNOS or NOS-2)] forms of NO synthase. In the present study we used the selective iNOS inhibitor aminoguanidine (AG) to evaluate the role of iNOS in modulating the pulmonary hypertension (PH) triggered by microparticle injections. Experiment 1 was conducted to confirm the ability of AG to inhibit NO synthesis by iNOS in broiler peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide (LPS, endotoxin). Mononuclear leukocytes treated with LPS produced 10-fold more NO than untreated (control) cells. The LPS-stimulated production of NO was partially inhibited by L-NAME and was fully inhibited by AG, thereby confirming that AG inhibits LPS-mediated iNOS activation in broilers. In Experiment 2 we evaluated the responses of male progeny from a base population (MP Base) and from a derivative line selected for one generation from the survivors of an LD50 microparticle injection (MP Select). The pulmonary arterial pressure (PAP) was lower in MP Select than in MP Base broilers. Both lines exhibited similar percentage increases in PAP after microparticles were injected, and AG modestly amplified the PH triggered by microparticles in both lines. In Experiment 3 we evaluated the responses of male progeny from a second base population (PAC Base) and from a derivative line selected for 3 generations using the unilateral pulmonary artery clamp technique (PAC Select). The PAP was lower in PAC Select than in PAC Base broilers, and both lines exhibited similar percentage increases in PAP in response to the microparticles. The PH triggered by microparticles was not amplified by AG but was doubled by L-NAME. These experiments demonstrate that during the 30 min following pulmonary vascular entrapment of microparticles, iNOS modulated the PH elicited in broilers derived from the MP pedigree line, but not in broilers from the PAC pedigree line. Different NOS-mediated responses among broiler populations may affect pulmonary hemodynamic characteristics of broiler lines selected using i.v. microparticle injections.
Commercial broilers are constantly exposed to airborne microorganisms and endotoxin (lipopolysaccharide, LPS). It has been shown that microbial contamination of the air was higher in broiler houses using floor litter than in broiler houses using netting-type floors. The current study evaluated the effect of housing conditions on blood leukocyte profiles and tested the hypothesis that, when compared to broilers reared in clean stainless steel cages (Cage group), broilers raised on floor litter (Floor group) should experience a higher environmental challenge and have a desensitized immune system that may exhibit better tolerance/resistance to subsequent intravenous LPS challenge. Hematological parameters were evaluated prior to and following i.v. administration of 1 mg/kg BW Salmonella typhimurium LPS (dissolved at 1 mg/0.25 mL in PBS) or i.v. injection of 0.25 mL/kg BW PBS alone. The results showed that prior to LPS/PBS injection, broilers in the cage group had higher heterophil and monocyte concentrations, a higher B cell percentage within the lymphocyte population, and a higher heterophil to lymphocyte (H:L) ratio in the blood. The i.v. LPS injection resulted in 25% mortality in the cage group and 42% mortality in the floor group within 8 h post-injection. LPS reduced the concentrations of total white blood cells (WBC) and all differential WBC except eosinophils and increased thrombocyte concentrations within 1 h post-injection in both groups. All of these values returned to their respective pre-injection levels within 48 h post-injection in the surviving birds. The two groups exhibited similar overall hematological changes after LPS injection except that the cage group showed a higher H:L ratio at 8 h post-injection and a lower B-cell percentage within the lymphocyte population at 48 h post-injection when compared with the floor group. We concluded that the immune systems of broilers reared on floor litter were desensitized and exhibited less pronounced leukocyte responses to i.v. LPS when compared with those of broilers reared in clean stainless steel cages. However, such desensitization of the immune system did not help broilers survive subsequent i.v. LPS challenge.
High retrograde pressure through the pulmonary venous system caused by failure of the left ventricle or left atrio-ventricular valve may result in the elevated pulmonary arterial pressure and right ventricular hypertrophy associated with pulmonary hypertension syndrome (PHS; ascites) in broiler chickens. In the present study, unanaesthetized male broilers from an ascites-resistant line, the base population from which the resistant line was derived, and a separate unselected line were used to determine whether changes in wedge pressure (thought to be similar to left atrial pressure) are predictive of differences in the pulmonary arterial pressure of clinically healthy and pre-ascitic broilers. Venous, right atrial, right ventricular, pulmonary arterial, and wedge pressures were obtained by inserting a catheter into a wing vein and progressively advancing the catheter into a pulmonary branch artery until the catheter tip became wedged in and occluded the flow through a terminal artery. Mean right ventricular and pulmonary arterial pressures were lower in the resistant line than in the base population, but wedge pressures did not differ between the resistant, base, and unselected lines. Right:total ventricular weight ratios (RV:TV) and the percentage saturation of hemoglobin with oxygen in arterial blood ranged in value from 0.18 to 0.44 and 65 to 96%, respectively. Wedge pressure, however, remained similar when pre-ascitic broilers with high RV:TV values and low oximetry values were compared with clinically healthy broilers. In all birds, whether healthy or showing pre-ascitic characteristics, the wedge pressure was slightly higher than the right atrial pressure but substantially lower than pulmonary arterial pressure. These observations provide definitive proof that pulmonary hypertension is initiated as a consequence of excessive pulmonary arterial or arteriole resistance. Pulmonary venous pressure is estimated by measuring the pulmonary arterial wedge pressure, and high wedge pressures would be evident if pulmonary hypertension was caused by the elevated downstream resistances associated with left-sided heart failure.
There has been extensive interest in the role of serotonin (5-hydoxytryptamine, 5-HT) in the pathogenesis of pulmonary hypertension because episodes of pulmonary arterial hypertension in humans have been linked to serotoninergic appetite-suppressant drugs. In this study, we investigated the role of serotonin in the development of pulmonary hypertension induced by intravenously injecting bacterial lipopolysaccharide (LPS, endotoxin) and cellulose microparticles. In experiment 1, we used a 5-HT ELISA kit for the in vitro quantitative determination of 5-HT in plasma during the development of pulmonary hypertension induced by injecting LPS and cellulose microparticles i.v. in broilers. In experiment 2, broilers were either chronically infused with 5-HT via surgically implanted osmotic pumps or received sham surgery as a control. After a period of 10 d, the pulmonary arterial pressure was recorded during challenge with injected LPS or microparticles. Microparticles elicited 5-HT plasma levels more than 2-fold greater than those elicited by LPS from 15 to 45 min postinjection. This indicates that 5-HT is an important mediator in the pulmonary hypertensive response of broilers to microparticles, but may not play a prominent role in the pulmonary hypertensive response to LPS. Furthermore, chronic 5-HT infusion via osmotic pumps caused an increase in the duration of the pulmonary hypertensive response of broilers to microparticles, indicating that the infused 5-HT was sequestered by circulating thrombocytes and then released upon microparticle-mediated thrombocyte activation. Serotonin appears to play a less prominent role in the pulmonary hypertensive response of broilers to LPS, indicating that other mediators within the innate response to inflammatory stimuli may also be involved. These results are consistent with our hypothesis that pulmonary arterial hypertension ensues when vasoconstrictors such as 5-HT overwhelm the dilatory affects of vasodilators such as nitric oxide, thereby effectively reducing the pulmonary vascular capacity of pulmonary arterial hypertension-susceptible broilers.
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