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Poult Sci 2007. 86:984-998
© 2007 Poultry Science Association
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SYMPOSIA: Metabolic and Cardiovascular Diseases in Poultry: Nutritional and Physiological Aspects

An Inadequate Pulmonary Vascular Capacity and Susceptibility to Pulmonary Arterial Hypertension in Broilers1

R. F. Wideman2, M. E. Chapman, K. R. Hamal, O. T. Bowen, A. G. Lorenzoni, G. F. Erf and N. B. Anthony

Department of Poultry Science, University of Arkansas, Fayetteville 72701

2 Corresponding author: rwideman{at}uark.edu


   ABSTRACT
TOP
 ABSTRACT
INADEQUATE PULMONARY VASCULAR...
 REDUCING THE PULMONARY VASCULAR...
 IMMUNE-MEDIATED VASODILATION AND...
 CONCLUSIONS
 REFERENCES
 
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 A2 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 TxA2 remains to be determined. Selecting broiler lines for resistance to PHS depends upon improving both anatomical and functional components of pulmonary vascular capacity.

Key Words: pulmonary hypertension • broiler • ascites • nitric oxide • serotonin


   INADEQUATE PULMONARY VASCULAR CAPACITY
TOP
 ABSTRACT
 INADEQUATE PULMONARY VASCULAR...
REDUCING THE PULMONARY VASCULAR...
 IMMUNE-MEDIATED VASODILATION AND...
 CONCLUSIONS
 REFERENCES
 
Our research has confirmed that the pulmonary vascular capacity of modern broilers is marginally adequate to accommodate the cardiac output (CO) required to support the metabolic demands incurred by fast growth and the extremes of environmental temperatures (Wideman, 2000, 2001). The pulmonary vascular capacity can be broadly defined to encompass metabolic limitations related to the tone (degree of contraction) maintained by the primary resistance vessels (pulmonary arterioles), as well as anatomical constraints related to the compliance and effective volume of the blood vessels (Figure 1Go; Wideman and Bottje, 1993). The pulmonary vasculature of broilers lacks functional elasticity (is marginally compliant) and is fully engorged with blood at a normal (resting) CO (Wideman and Kirby, 1995b; Wideman et al., 1996a,b). Consequently, the compensatory mechanisms known to minimize pulmonary vascular resistance (PVR) in mammals, such as arteriole dilation, capillary distention, and recruitment of previously underperfused vascular channels, appear to be minimally effective in broilers. Broilers possessing the most limited pulmonary vascular capacity develop pulmonary arterial hypertension (PAH), leading to terminal pulmonary hypertension syndrome (PHS; also known as ascites syndrome) when the right ventricle must develop an excessively elevated pulmonary arterial pressure (PAP) to propel the requisite CO through the lungs (Wideman and Bottje, 1993; Wideman, 2000, 2001; Wideman and Kirby, 1995a,b, 1996; Wideman et al., 1996a,b, 1997; Wideman and French, 1999). Higher PVR and CO values have been recorded in broilers with PAH than in clinically healthy individuals (Wideman and Tackett, 2000; Wideman et al., 2000; Lorenzoni and Wideman, unpublished data). Pulmonary arterial catheterization of apparently healthy broilers demonstrates that PAH precedes right ventricular hypertrophy (Wideman et al., 2006). Subsequent specific right ventricular "work hypertrophy" (increased mass of the free wall of the right ventricle) and elevated right ventricular weight-total ventricular weight (RV:TV) ratios consistently demonstrate the central role of pulmonary hypertension in the pathogenesis of PHS (Ploog, 1973; Cueva et al., 1974; Huchzermeyer and DeRuyck, 1986; Guthrie et al., 1987; Julian et al., 1987; Huchzermeyer et al., 1988; Julian, 1988, 1989, 1993; Lubritz et al., 1995; Owen et al., 1995a; Wideman and French, 1999; Wideman, 2000). Wedge pressures uniformly lower than 15 mmHg are obtained during pulmonary arterial catheterizations of broilers having PAP values ranging from 16 to 55 mmHg and corresponding RV:TV ranging from 0.20 to 0.51 (Chapman and Wideman, 2001; Wideman, 2001; Lorenzoni and Wideman, unpublished data). Wedge pressures ≤15 mmHg coupled with PAP ≥25 mmHg are specifically diagnostic for PAH attributable to elevated arteriole (precapillary) resistance. In contrast, wedge pressures exceed 15 mmHg and increase in direct proportion to increases in PAP when pulmonary venous hypertension is triggered by elevated postcapillary (venous) resistance attributable to mitral valve insufficiency or congestive heart failure (Dawson and Linehan, 1997; Hermo-Weiler et al., 1998; Chapman and Wideman, 2001; Chemla et al., 2002; Deboeck et al., 2004; Benza and Tallaj, 2006). The crucial contribution of elevated precapillary resistance during the terminal pathogenesis of PHS can be deduced from consistent observations of medial muscle layer hypertrophy in the pulmonary arterioles of broilers developing clinical ascites (Cueva et al., 1974; Sillau and Montalvo, 1982; Huchzermeyer and DeRuyck, 1986; Hernandez, 1987; Julian, 1988; Peacock et al., 1989; Maxwell, 1991; Enkvetchakul et al., 1995; Xiang et al., 2002, 2004; Moreno de Sandino and Hernandez, 2003, 2006; Tan et al., 2005). Following the onset of PAH, the pathophysiological progression of PHS includes the gradual onset of systemic arterial hypoxemia (reduced partial pressure of O2 on arterial blood) and hypercapnia (elevated partial pressure of CO2 in arterial blood), polycythemia (increased hematocrit), reductions in total peripheral resistance and mean systemic arterial pressure, regurgitation by the monocuspid right atrioventricular valve, right-sided congestive heart failure, central venous hypertension, hepatic cirrhosis, and transudation of plasma from the surface of the liver into the abdominal cavity (ascites; Ploog, 1973; Wideman, 1984, 1988, 1999, 2000, 2001; Huchzermeyer and DeRuyck, 1986; Julian et al., 1987; Julian, 1988, 1993; Peacock et al., 1989, 1990; Julian and Mirsalimi, 1992; Wideman and Bottje, 1993; Fedde and Wideman, 1996; Forman and Wideman, 1999; Wideman et al., 1999b, 2000; Wideman and Tackett, 2000; Balog, 2003). The onset of hypoxemia and hypercapnia serve as reliable predictive indices that apparently healthy broilers will develop ascites (Peacock et al., 1989; Julian and Mirsalimi, 1992; Roush et al., 1996, 1997; Kirby et al., 1997; Wideman et al., 1998c, 2000). All major broiler genetics companies routinely use pulse oximetry to eliminate hypoxemic individuals from their pedigree lines and thereby markedly improve resistance to PHS. The spontaneous onset of hypoxemia and hypercapnia cannot be attributed to low atmospheric O2 (hypoxia), poor circulation, anemia, intracardiac right to left shunts, hypoventilation, impaired respiratory function per se, or intrapulmonary vascular shunts through unventilated regions of the lungs. Instead, hypoxemia and hypercapnia are attributable to the onset of a diffusion limitation (West, 1993) that is revealed when erythrocytes are forced to flow too rapidly past the pulmonary gas exchange surfaces to permit full blood-gas equilibration of O2 and CO2 (Henry and Fedde, 1970; Peacock et al., 1989, 1990; Reeves et al., 1991; Wideman and Kirby, 1995a,b; Wideman et al., 1996a,b, 2000; Fedde et al., 1998; Forman and Wideman, 1999; Wideman and Tackett, 2000).


Figure 1
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  		Figure 1. The pulmonary vascular (P-V) capacity encompasses anatomical components such as the compliance (elasticity), volume, and cumulative cross-sectional radius of the blood vessels, as well as functional components including vascular responsiveness to vasoactive mediators affecting the tone maintained by the primary resistance vessels. Pulmonary arterial pressure (PAP) is (approximately) equal to the cardiac output (CO) multiplied by the pulmonary vascular resistance (PVR). Resistance to flow through blood vessels is principally determined by the vessels’ radius (r4) rather than by length (L) or the viscosity of blood ({eta}). Increases in PAP can be attributed to increases in CO, to anatomical inadequacies of pulmonary vascular capacity (increased PVR), or excessive vasoconstriction (increased PVR; adapted from Wideman and Bottje, 1993).

 

   REDUCING THE PULMONARY VASCULAR CAPACITY TRIGGERS PAH AND PHS
TOP
 ABSTRACT
 INADEQUATE PULMONARY VASCULAR...
 REDUCING THE PULMONARY VASCULAR...
IMMUNE-MEDIATED VASODILATION AND...
 CONCLUSIONS
 REFERENCES
 
If an inadequate pulmonary vascular capacity is a primary determinant of susceptibility to PHS, then experimentally reducing the pulmonary vascular capacity should initiate the pathophysiological progression leading to terminal PHS (Figure 2Go; Powell et al., 1985; Wideman and Bottje, 1993). Indeed, acutely tightening a snare to occlude 1 pulmonary artery halves the pulmonary vascular capacity, doubles the PVR, and forces the right ventricle to double the PAP to propel the entire CO through the unoccluded lung. Increasing the blood flow through 1 lung during acute unilateral pulmonary artery occlusion triggers a diffusion limitation resulting in the immediate onset of systemic arterial hypoxemia and hypercapnia. All of the responses to tightening a snare around 1 pulmonary artery are restored to their original baseline values within 5 min after the snare is released (Wideman and Kirby, 1995b; Wideman et al., 1996a,b, 1998a, 1999b; Forman and Wideman, 1999, 2001). Chronic unilateral pulmonary artery occlusion, accomplished by surgically obstructing 1 pulmonary artery with a silver clip, triggers the entire pathogenesis observed in broilers spontaneously developing PHS (Wideman and Kirby, 1995a, 1996; Wideman et al., 1997; Ruiz-Feria et al., 1999; Forman and Wideman, 2001). The survivors of chronic unilateral pulmonary artery occlusion possess a pulmonary vascular capacity sufficient to accommodate the combined challenges of an elevated PVR, a disproportionately high rate of blood flow through the unoccluded lung, and sustained PAH. Broiler breeders that thrive in spite of having 1 pulmonary artery occluded subsequently produce progeny exhibiting reduced PAP (Figure 3Go) and low RV:TV values combined with a cumulative 90% reduction in susceptibility to PHS when grown as rapidly as possible during exposure to cool temperatures (Wideman and French, 1999, 2000; Chapman and Wideman, 2001; Wideman et al., 2006). This dramatic progress within 2 generations of selection demonstrates that selection pressure rigorously focused to challenge the pulmonary vascular capacity eliminates genes coding for a highly significant proportion of the PHS susceptibility in commercial broilers (Wideman, 2001). Our success has been achieved by identifying and then directly addressing the central pathogenic mechanisms expressed by preascitic (susceptible) broilers (e.g., PAH, hypoxemia, elevated RV:TV) instead of focusing on the downstream manifestations and pathologies expressed by chronically deteriorating individuals succumbing to clinical ascites.


Figure 2
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  		Figure 2. When the pulmonary vasculature is relatively noncompliant and fully engorged with blood, then experimentally reducing the pulmonary vascular (P-V) capacity by occluding 1 pulmonary artery doubles the pulmonary vascular resistance (PVR) and forces the right ventricle to double the pulmonary arterial pressure (PAP) to propel the entire cardiac output (CO) through the unoccluded lung. The rapid (within minutes) onset of systemic arterial hypoxemia (reduced partial pressure of O2 on arterial blood) and hypercapnia (elevated partial pressure of CO2 in arterial blood) are attributable to the onset of a diffusion limitation that is revealed when erythrocytes [red blood cells (RBC)] are forced to flow too rapidly past the pulmonary gas exchange surfaces to permit full blood-gas equilibration of O2 and CO2. Hypoxemia dilates the systemic vascular resistance vessels, reducing total peripheral resistance (TPR) and thus the mean systemic arterial pressure (MAP; adapted from Wideman, 2001).

 

Figure 3
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  		Figure 3. Distributions of pulmonary arterial pressure (PAP) values obtained from individual male broilers from 7 lines: a base population (Particle Base) and a derivative line selected for 1 generation from the survivors of a 50% lethal dose microparticle injection (Particle Resistant); a second base population (PAC Base) and a derivative line selected for 3 generations using the unilateral pulmonary artery clamp technique (PAC Resistant); and susceptible, resistant, and relaxed lines selected for 10 generations under conditions of hypobaric hypoxia (Hypobaric Susceptible, Resistant, and Relaxed). The mean value for each line is indicated by X. Different letters (a,b,c) designate means that differed within respective selection techniques (P < 0.05; Wideman et al., 2006; Bowen et al., 2006a).

 
Surgical occlusion of 1 pulmonary artery is impractical for large-scale genetic selection programs. Accordingly, we developed a technique in which microparticles having a size suitable for occluding precapillary arterioles are injected into a systemic vein to be carried to the lungs by the returning venous blood [US patent 6,720,473 protects the exclusive rights of the University of Arkansas to all uses of the i.v. microparticle injection technology within the context of evaluating or affecting the pulmonary vascular capacity, pulmonary vascular resistance, pulmonary hypertension, cardiopulmonary hemodynamics, and susceptibility to PHS (ascites) in domesticated animal species]. Pulmonary arterioles become occluded in proportion to the number and size of the microparticles injected, thereby increasing the PVR and triggering acute physiological responses that mirror those previously observed following acute unilateral pulmonary artery occlusion and that are characteristic of preascitic broilers (Wideman and Erf, 2002; Wideman et al., 2005b, 2006). After injecting a suitable dose of microparticles, broilers with the most limited pulmonary vascular capacity rapidly succumb to respiratory insufficiency (acute postinjection mortality); those with a marginal pulmonary vascular capacity develop hypoxemia, hypercapnia, and PAH, leading to terminal PHS; and those having a sufficiently robust pulmonary vascular capacity thrive as clinically healthy and resistant survivors (Figure 4Go; Wideman et al., 2002). The combined mortality (acute postinjection + ascites mortality) is proportional to the quantity of microparticles injected and the magnitude of the resulting sustained pulmonary hypertensive response. Broiler lines selected for PHS resistance are substantially more resistant to microparticle injections when compared with their respective unselected (base) populations or PHS-susceptible lines (Figure 4Go; Wideman et al., 2002). Microparticle injections currently are being used to select commercial broiler lines having a robust pulmonary vascular capacity and improved resistance to PHS. For every commercial and experimental population evaluated to date, broilers from lines known to be resistant to the spontaneous onset of PHS exhibit significantly lower mortality when injected i.v. with microparticle doses that trigger high mortality among broilers from susceptible lines. Breeder parent survivors of microparticle injections produce progeny exhibiting reduced PAP (Figure 3Go) and RV:TV values as well as reduced susceptibility to PHS when challenged with cool temperature exposure (Wideman et al., 2002, 2006; Wideman, unpublished data). Microparticle injections also can be used to select broilers whose robust cardiopulmonary capacity confers improved growth and livability during exposure to heat stress (Wideman et al., 2003a), thereby reemphasizing the requirement for the lungs to accommodate the increases in CO necessary to deliver additional O2 to the tissues whenever broilers are subjected to nonthermoneutral temperatures (Wideman, 1999, 2000).


Figure 4
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  		Figure 4. Male broilers from a base population (Base Population Males) and a derivative line selected for 2 generations using the unilateral pulmonary artery clamp technique (PHS-Resistant Males) were injected on d 20 with 0.4 mL of a cellulose microparticle suspension (0.02 g/mL) and then maintained at a thermoneutral temperature in an environmental chamber until d 49. Diagnostic categories include the following: ascites syndrome (A), 24 h postinjection mortality (P-I), total susceptibility index (TSI; TSI = A + P-I), and nonascitic (N; normal, clinically healthy) through the end of the experiment. Numbers in parentheses reflect the affected/total evaluated; probability values are for interline comparisons within a diagnostic category (Wideman et al., 2002).

 

   IMMUNE-MEDIATED VASODILATION AND VASOCONSTRICTION
TOP
 ABSTRACT
 INADEQUATE PULMONARY VASCULAR...
 REDUCING THE PULMONARY VASCULAR...
 IMMUNE-MEDIATED VASODILATION AND...
CONCLUSIONS
 REFERENCES
 
Role of NO

Physical occlusion of precapillary arterioles is not the only mechanism by which microparticles can influence the pulmonary vascular resistance. Within minutes after being injected, the entrapped microparticles are surrounded by focal aggregates of thrombocytes and by monocytes and macrophages infiltrating the perivascular region. Within 24 to 48 h, lymphoid aggregates form around occluded vessels (Figure 5Go; Wideman et al., 2002; Wang et al., 2003). This dynamic intrapulmonary inflammatory response potentially can trigger the leukocytes and adjacent vascular endothelium to synthesize and release potent vasoactive compounds near the vascular smooth muscle (Figure 6Go; Wideman, 2001; Wideman et al., 2004). Of specific interest is the synthesis of NO by the enzyme NO synthase (NOS), which is constitutively expressed in vascular endothelial cells [endothelial NOS (eNOS) or NOS-3] or is induced in activated monocytes and macrophages [inducible NOS (iNOS) or NOS-2; Chang et al., 1996; Hussain and Qureshi, 1997, 1998; Dil and Qureshi, 2002a,b; Qureshi, 2003]. In chickens, NO dilates the pulmonary vasculature and attenuates (modulates) the production, release, and vascular responsiveness to vasoconstrictors (Figure 6Go). When both eNOS and iNOS are inhibited by N{omega}-nitro-L-Arg methyl ester (L-NAME), the ensuing reduction in NO synthesis leads to pulmonary arterial vasoconstriction, PAH, and PHS (Wideman et al., 1995, 1996a, 1998a, 2004; Grabarevic et al., 1997; Martinez-Lemus et al., 1999, 2003; Ruiz-Feria et al., 2001; Villamor et al., 2002; Wang et al., 2002c; Weidong et al., 2002; Odom et al., 2004; Wideman and Chapman, 2004). Pretreating broilers with L-NAME doubles the increases in PAP and PVR elicited by subsequent microparticle injections (Figure 7Go). Similarly, the mortality triggered within 48 h after injecting microparticles more than doubles when L-NAME is combined with microparticle injection doses that otherwise cause relatively low mortality in the absence of L-NAME (Figure 8Go; Wideman et al., 2005b). The magnitude and duration of the microparticle-induced systemic arterial hypoxemia remains unaffected by L-NAME, indicating that hypoxemia per se contributes minimally to PAH and postinjection mortality (Wideman et al., 2005b), replicating previous evidence that PAH and PHS attributable to unilateral pulmonary artery or bronchus occlusion are not directly attributable to hypoxemia and hypercapnia per se (Wideman et al., 1996b, 1997). Pretreating broilers with the selective iNOS inhibitor aminoguanidine marginally amplifies the increase in PAP elicited by microparticle injections in progeny from the survivors of a 50% lethal dose microparticle selection (Figure 9Go), but not in progeny from survivors of unilateral pulmonary artery occlusion (Wideman et al., 2006). Expression of iNOS by activated monocytes and macrophages responding to microparticles entrapped in the lungs requires hours rather than minutes (Hamal et al., 2006). The levels of NO produced in response to microparticle entrapment are sufficient to elicit local vasodilation (Wideman et al., 2005b, 2006) but insufficient to elevate total NO concentrations in the systemic circulation (Bowen et al., 2006b). Indeed, when the combined processes of NO dilution in extracellular fluid, NO binding to hemoglobin, NO exhalation as a gas, and rapid renal clearance are taken into consideration, it becomes evident that low levels of NO capable of effectively relaxing vascular smooth muscle need not significantly elevate total plasma NO concentrations (Chapman and Wideman, 2006a). The current evidence indicates that NO, generated acutely by eNOS and subsequently supplemented when iNOS is expressed, performs dual roles as a vasodilator and a modulator of the production, release and vascular responsiveness to vasoconstrictors (Figure 6Go; Wideman et al., 2002, 2004, 2005b, 2006). Broiler lines undergoing selection for improved resistance to PHS should be monitored for potential coselection of eNOS and iNOS expression. For example, broilers are most likely to survive microparticle injections if their endothelial cells express more eNOS and if their leukocytes possess inflammatory response profiles that have been shifted toward enhanced recognition and removal activity (more rapid clearance of particles from the vasculature), enhanced vasodilator production (e.g., increased iNOS expression), and attenuated vasoconstrictor production (Wideman et al., 2004, 2005b). Reduced pulmonary arteriole eNOS expression has been reported in broilers developing PHS during chronic exposure to hypobaric hypoxia (Moreno de Sandino and Hernandez, 2003, 2006), but pulmonary eNOS and iNOS expression levels have not been associated with the onset of PHS induced by chronic exposure to subthermoneutral temperatures (Teshfam et al., 2006).


Figure 5
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  		Figure 5. Intrapulmonary inflammatory response of male broilers injected i.v. at 22 d of age with 0.3 mL of cellulose microparticles. (Top panel) Hematoxylin and eosin staining of lung tissue obtained 20 min postinjection showing a cellulose microparticle (arrow) entrapped in a pulmonary arteriole surrounded by aggregating nucleated thrombocytes (T). Nucleated erythrocytes (e) are found in blood capillaries surrounding air (a) capillaries. (Bottom panel) Hematoxylin and eosin staining of lung tissue collected 48 h postinjection showing a lymphoid aggregate adjacent to 2 cellulose microparticles (arrows) within intraparabronchial arterioles. The occluded vessels are surrounded by granulomatous tissue consisting primarily of macrophages, including giant cells, and fibrous tissue (Wideman et al., 2002; Wang et al., 2003).

 

Figure 6
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  		Figure 6. Microparticle occlusion of pulmonary arterioles increases blood flow and shear stress through unoccluded channels, with the resulting increase in shear stress activating endothelial NO synthase (eNOS) to produce the potent vasodilator NO as well as the putative eicosanoid vasodilators prostacyclin (PGI2) and prostaglandin E2 (PGE2). Entrapped microparticles activate monocytes and macrophages, triggering a cascade of intracellular signaling events including the release of platelet-activating factor (PAF) and expression of inducible NO synthase (iNOS). Entrapped microparticles and PAF stimulate thrombocytes to release the pulmonary vasoconstrictors thromboxane (TxA2) and serotonin [5-hydroxytryptamine (5-HT)]. The iNOS enzyme produces copious quantities of NO and derivative reactive O2-N species [e.g., nitrite (NO3–) and peroxynitrite (OONO–)] that are nonspecifically cytotoxic. Nitric oxide relaxes pulmonary vascular smooth muscle, NO modulates (inhibits) PAF activation of thrombocytes and the release of TxA2 and 5-HT, and NO and PGI2 inhibit platelet aggregation and the formation of obstructive microthrombi. Vascular remodeling (hypertrophy, hyperplasia, and distal extension of pulmonary arteriole smooth muscle cells) is inhibited by NO (Tan et al., 2005), whereas 5-HT stimulates vascular remodeling. cGMP = cyclic guanosine monophosphate (adapted from Wideman et al., 2004).

 

Figure 7
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  		Figure 7. Pulmonary arterial pressure (PAP) and relative pulmonary vascular resistance (PVR) for male broilers pretreated with saline (control) or the NO synthase inhibitor N{omega}-nitro-L-Arg methyl ester (L-NAME) followed by i.v. injections of cellulose microparticles (mean ± SEM, n = 12/ group). Data were averaged electronically during representative sample intervals at 4, 2, and 0.5 min before injecting saline or L-NAME (control sample intervals C1, C2, and C3, respectively); at 0.5, 2.5, and 5 min after injecting saline or L-NAME (L-NAME sample intervals LN1, LN2, and LN3, respectively); at 0.5, 1, 1.5, 2, 4, 6, 8, 10, 15, 20, 25, and 30 min after the cellulose microparticle injection (sample intervals MP1 through MP12, respectively); and during the peak PAP responses that occurred within 90 s (peak 1) and 4 to 6 min (peak 2) after the microparticle injection. Asterisks (*) denote values that differ from the preinjection values (C1, C2, C3) within a group (P ≤ 0.05). Different letters (a,b) designate group means that differed within a time interval (P ≤ 0.05; Wideman et al., 2005b).

 

Figure 8
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  		Figure 8. Mortality percentages for male broilers injected at 3 wk of age with the following: saline (Saline Control); N{omega}-nitro-L-Arg methyl ester (L-NAME Control); 0.3 mL of microparticles (0.3 Particles); 0.3 mL of microparticles and L-NAME (0.3 Particles + L-NAME); 0.4 mL of microparticles (0.4 Particles); or 0.4 mL of microparticles and L-NAME (0.4 Particles + L-NAME). Male broilers also were injected at 7 wk of age with 0.70 mL of microparticles alone (0.7 Particles) or in combination with L-NAME (0.7 Particles + L-NAME). Different letters (a,b,c,d) designate mortality incidences that differed (P ≤ 0.05) among groups (Wideman et al., 2005b).

 

Figure 9
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  		Figure 9. Pulmonary arterial pressures (PAP) are shown for progeny from the survivors of a 50% lethal dose microparticle selection pretreated with saline (control) or aminoguanidine followed by i.v. injections of cellulose microparticles. Data were averaged electronically during representative sample intervals at 4, 2, and 0.5 min before injecting saline or aminoguanidine (sample intervals C1, C2, and C3); within 0.5 min after injecting saline or aminoguanidine (AG1) and at 2-min intervals throughout the subsequent 15 min (sample intervals AG2 to AG8); within 0.5, 1, 1.5, 2, 4, 6, 8, 10, 15, 20, 25, and 30 min after injecting cellulose microparticles (sample intervals MP1 through MP12, respectively); and during the minor and major peak responses (peaks 1 and 2; mean ± SEM, n = 18 per group). Asterisks (*) denote the earliest postinjection values that were higher than the respective preinjection values (C3 vs. AG1 to AG8, or AG8 vs. MP1 to MP12) within a group (P ≤ 0.05). Probability values that approached but did not attain significance at P ≤ 0.05 also are indicated (Wideman et al., 2006).

 
Role of Serotonin (5-Hydroxytryptamine)

Nucleated avian thrombocytes are the most numerous leukocytes in avian blood and are functional homologs of mammalian platelets. Thrombocytes accumulate serotonin [5-hydroxytryptamine (5-HT)] within intracellular storage granules that are released upon thrombocyte activation and aggregation (Inouye et al., 1969; Kimura, 1969; Kuruma et al., 1970; Simoneit et al., 1970; Sorimachi et al., 1970, 1974; Meyer and Sturkie, 1974; Cox, 1985; Lacoste-Eleaume et al., 1994). Serotonin autostimulates thrombocyte activation and aggregation (Belamarich et al., 1968; Belamarich and Simoneit, 1973), and activated avian thrombocytes are phagocytic toward microparticulates and bacteria (Glick et al., 1964; Carlson et al., 1968; Sterz and Weiss, 1973; Chang and Hamilton, 1979a,b; Awadhiya et al., 1980; Ohata and Ito, 1986; Lam, 1997; DaMatta et al., 1998; Roland and Birrenkott, 1998; Wigley et al., 1999). Thrombocytes rapidly surround microparticles entrapped in intimate proximity to pulmonary arteriole smooth muscle, providing an ideal milieu in which the vasoconstrictors 5-HT and thromboxane A2 (TxA2) can further amplify increases in PVR caused by physical occlusion (Figures 5Go and 6Go). Serotonin increases the PVR and PAP in broilers and is singularly the most potent pulmonary vasoconstrictor we have evaluated. Serotonin is capable of triggering essentially instantaneous and fully obstructive vasoconstriction, leading to an immediate >90% reduction in CO and terminal suffocation within 30 s in clinically healthy broilers unless i.v. infusion rates are carefully titrated to at least 10-fold lower than levels typically used to elicit PAH in mammals (Chapman and Wideman, 2002). The pulmonary hemodynamic responses to 5-HT recently were evaluated in broilers pre-treated with the selective 5-HT2A receptor antagonist ketanserin or with the nonselective 5-HT1/2 receptor antagonist methiothepin. Ketanserin has high affinity for the 5-HT2A receptor but also binds less potently to the 5-HT2C, 5-HT2B, 5-HT1D, adrenergic, and dopamine receptors (Barnes and Sharp, 1999). Methiothepin is a nonselective 5-HT1 and 5-HT2, as well as a 5-HT5–7 receptor antagonist with varying degrees of selectivity; however, it displays high affinities for 5-HT1A and 5-HT1B receptor subtypes in rats (Engel et al., 1986). Pretreating broilers with ketanserin failed to alter the PAH response to subsequent 5-HT infusion, whereas pretreatment with methiothepin reduced PAP below baseline values and virtually eliminated increases in PVR and PAP elicited by 5-HT (Figure 10Go). Methiothepin clearly blocked 5-HT-mediated increases in PVR and PAP in broilers, although the specific receptor subtype involved remains to be determined (Chapman and Wideman, 2006b). In a subsequent study by Chapman and Wideman (2006c), methiothepin was used to evaluate the role of 5-HT in the onset of PAH triggered by i.v. microparticle or lipopolysaccharide injections. Pretreatment with methiothepin reduceed PAP below baseline values, demonstrating that 5-HT likely exerts tonic control of PVR. Microparticle injections increased PAP by 90% within 10 min in untreated (control) broilers, but the same dose of microparticles failed to significantly elevate PAP in broilers that were pretreated with methiothepin (Figure 11Go). Injecting a high dose of microparticles (1.0 mL of 0.02 g/mL) into broilers from a PHS-susceptible line (Anthony et al., 2001) elicited 78% mortality in untreated controls as compared with only 20% in those pretreated with methiothepin (Chapman and Wideman, 2006c). Injecting the same microparticle dose into a PHS-resistant line (Anthony et al., 2001) elicited 12% mortality in untreated controls as compared with zero mortality in those pretreated with methiothepin (Chapman and Wideman, 2006c). Methiothepin had minimal effect on lipopolysaccharide-mediated PAH (Chapman and Wideman, 2006c). All available evidence supports the hypothesis that 5-HT plays a key role in maintaining the basal tone of the pulmonary vasculature and a dominant role in the increases in PVR and PAP elicited by microparticle injections (Chapman and Wideman, 2006b,c).


Figure 10
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  		Figure 10. Pulmonary arterial pressure (PAP) in male broilers pretreated with saline (control) or the serotonin receptor inhibitor methiothepin, followed by i.v. infusion of serotonin. Data were averaged electronically during representative sample intervals at the start of data collection and at 5-min intervals thereafter (St, S5, S10); within 0.5 min after injecting saline or methiothepin and at 5-min intervals thereafter (X, X5, X10); within 0.5 min after the beginning of serotonin infusion and at 5-min intervals thereafter (Se, Se5, Se10); and within 5 min after stopping the serotonin infusion and at 5-min intervals thereafter (E, E5, E10; mean ± SEM, n = 20 per group). Asterisks (*) designate group means that differed within a sample interval (P ≤ 0.05). Different letters (a,b,c,d,e) designate values that differed within a group across sample intervals (P ≤ 0.05; Chapman and Wideman, 2006a).

 

Figure 11
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  		Figure 11. Percentage change in pulmonary arterial pressure (PAP) in male broilers pretreated with saline (control) or the serotonin receptor inhibitor methiothepin, followed by i.v. injections of cellulose microparticles. Data were averaged electronically during representative sample intervals at the start of data collection and at 5-min intervals thereafter (St, S5, S10); within 0.5 min after injecting saline or methiothepin and at 5-min intervals thereafter (M, M5, M10); and within 0.5 min after microparticle injection and at 5-min intervals thereafter (L to L40; mean ± SEM, n = 15/group). Asterisks (*) denote values that were higher than the respective preinjection (St to S10) values within a group (P ≤ 0.05). Different letters (a,b,c) designate group means that differed within a sample interval (P ≤ 0.05; Chapman and Wideman, 2006b).

 

   CONCLUSIONS
TOP
 ABSTRACT
 INADEQUATE PULMONARY VASCULAR...
 REDUCING THE PULMONARY VASCULAR...
 IMMUNE-MEDIATED VASODILATION AND...
 CONCLUSIONS
REFERENCES
 
Selecting broiler lines for improved resistance to PHS currently appears to depend upon improving both anatomical and functional components of pulmonary vascular capacity. Our observations are consistent with the model illustrated in Figure 6Go. We have confirmed that sufficient NO can be produced (initially by eNOS but subsequently supplemented by iNOS over prolonged periods) during pulmonary inflammatory challenges to perform the dual roles of dilating the pulmonary vasculature as well as modulating the production, biological effect, or both, of concurrently induced vasoconstrictors (Wideman and Chapman, 2004; Wideman et al., 2005b, 2006; Bowen et al., 2006a,c; Chapman and Wideman, 2006a). We do not know whether NO accomplishes its principal protective role by dilating the pulmonary arterioles or by modulating the release of vasoconstrictors by thrombocytes. The eicosanoid vasodilators prostacyclin (PGI2) and prostaglandin E2 do not reduce PVR when infused i.v. into clinically healthy broilers, broilers whose pulmonary vasculature has been preconstricted with arachidonic acid, or broilers with preexisting PAH (Wideman et al., 2005a, unpublished data). Accordingly, PGI2 and prostaglandin E2 do not appear to dilate the pulmonary vasculature in broilers, although PGI2 may significantly modulate thrombocyte activation (Wideman et al., 2004, 2005a). Thromboxane A2, whether administered i.v. as the potent TxA2 mimetic U44069 [GenBank] or produced by circulating thrombocytes, consistently causes pulmonary vasoconstriction and PAH in broilers. The precise contribution of TxA2 to increases in PVR in PHS-susceptible broilers remains to be determined (Wideman et al., 1998b, 1999a, 2001, 2004, 2005a; Chapman and Wideman, 2006b). Serotonin clearly plays a key role in increasing the basal tone (partial state of contracture) of the pulmonary resistance vessels and a dominant role in microparticle-induced increases in PVR and PAP in broilers (Chapman and Wideman, 2002, 2006b,Chapman and Wideman, c). It currently appears likely that microparticle selection serves to eliminate individuals having excessive 5-HT biosynthesis, inhibited thrombocyte uptake or enhanced release of 5-HT, enhanced receptor-mediated vasoconstrictive responsiveness to 5-HT, or altered internalization of 5-HT by a specific transporter. Accordingly, it currently is our hypothesis that susceptibility to PHS is a consequence of an anatomically inadequate pulmonary vascular capacity combined with the functional predominance of vasoconstriction attributable to 5-HT over vasodilation and immune modulation attributable to NO. Indeed, studies focused on the fundamental basis for pulmonary hypertension in human patients repeatedly implicate 5-HT in the pathogenesis of idiopathic PAH (MacLean et al., 2000; Eddahibi et al., 2001; Marcos et al., 2003, 2004; Eddahibi and Adnot, 2005; Lawrie et al., 2005), PAH triggered by serotonergic appetite suppressant drugs (Seiler et al., 1974; Abenhaim et al., 1996; Eddahibi and Adnot, 2002; Naeije and Eddahibi, 2004), PAH initiated by hypoxia and monocrotaline toxin (Eddahibi et al., 1997, 1999, 2000; Marcos et al., 2003; Guignabert et al., 2005), and PAH associated with gram-negative sepsis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and other inducers of secondary PAH in humans (Sibbald et al., 1980; Heffner and Repine, 1997; Egermayer et al., 1999; MacLean et al., 2000; Eddahibi et al., 2003).


   ACKNOWLEDGMENTS
 
This research was supported by USDA/CSREES/NRI grant 2003-35204-13392.


   FOOTNOTES
 
1 Presented as part of the Metabolic and Cardiovascular Disease Symposium, July 19, 2006, at the Poultry Science Association Meeting, Edmonton, Alberta, Canada. Back

Received for publication October 30, 2006. Accepted for publication November 19, 2006.


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