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PGE(2) has centrally mediated respiratory, febrile, and cardiovascular effects that markedly differ between fetal and adult life. We hypothesized that the transition from fetal to adult responses to PGE(2) occurs in the newborn period. Thus effects of an intracarotid infusion of PGE(2) (3 microg/min for 60 min) were determined in unanesthetized new...
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... lambs (Fig. 4). Breathing resumed with a markedly abnormal AF pattern (Fig. 4) that was likely the result of the sudden and marked increase in the peak amplitude of the phasic TAEMG activity that also occurred at this time (Fig. 5). Most of the increase in TAEMG activity occurred during early expiration when alterations in AF were most marked (Fig. 6). Increased TAEMG activity and AF disruptions, however, were sometimes also observed during inspiration (Fig. ...
Citations
... For instance, owing to the limited number of recordings per condition, we could not stratify our data by postnatal age. But in rats and sheep, sensitivity to PGE2-induced apnea is strongest immediately at birth and levels off with postnatal age-as early as P2-P4 in rats and P15 in sheep (Tai and Adamson, 2000;Ballanyi, 2004). Thus, it is plausible that the different responses to PGE2 between strains reflect variation in early postnatal development. ...
Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior in vivo. Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1–10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R (Ptger2) were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (Ptger3). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1–10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors.
... For instance, owing to the limited number of recordings per condition, we could not stratify our data by postnatal age. But in rats and sheep, sensitivity to PGE2-induced apnea is strongest immediately at birth and levels off with postnatal age-as early as P2-P4 in rats and P15 in sheep (Tai and Adamson, 2000;Ballanyi, 2004). Thus, it is plausible that the different responses to PGE2 between strains reflect variation in early postnatal development. ...
Inflammation in newborn infants can cause respiratory dysfunction and is potentially life-threatening. Specifically, high levels of Prostaglandin E2 (PGE2) depress breathing and increase the frequency of apneas. PGE2 modulates rhythmic inspiratory-related activity generated by the pre-Bötzinger Complex (pre-BötC), but there have been conflicting reports about whether PGE2 inhibits or augments inspiratory-related rhythm generation in vitro. The binding affinities of Prostaglandin EP receptor subtypes 3 and 4 (EP3R/EP4R) are two orders of magnitude higher than those of subtypes 1 and 2 (EP1R/EP2R). Therefore, ambiguous effects of PGE2 on inspiratory rhythm generation might be explained by differences in PGE2 concentration, which would differentially activate EP receptor subtypes. We measured the effect of PGE2 (1nM to 1µM) on the fictive inspiratory motor output of acute medullary brainstem slices containing the pre-BötC. Integrated hypoglossal nerve (XII) output exhibited a biphasic dose response to increasing concentrations of PGE2. Nanomolar concentrations decreased the frequency of inspiratory-related motor output, while micromolar concentrations increased inspiratory frequency. Subtype-specific pharmacological blockade and activation of EP receptors suggest that both EP2R and EP3R mediate the effects of PGE2 on the frequency of XII output in an opposing fashion. These data resolve previous conflicting reports on PGE2's modulatory role in the pre-BötC and open new avenues for pharmacological intervention in neonatal respiratory distress. For instance, it might be possible to leverage the antagonistic action of EP2R and EP3R to treat breathing dysfunction caused by neonatal inflammation.
... [16,34] When microsomal prostaglandin E2 synthase-1 (mPGES-1) and cyclooxygenase-2 (COX-2) activity gets induced through the production of CCL2 and proinflammatory substances such as IL-1beta [35] and induction of NF-kB pathway, [19] PGE2 is released into the brain parenchyma. [36] This may regulate several central effects including anorexia, [37] respiratory depression, [38] fever, [39] and pain. [40] Furthermore, hypoxia can also induce PGE2 synthesis by the ...
The outbreak of a new, potentially fatal virus, SARS‐COV‐2, which started in December 2019 in Wuhan, China, and since developed into a pandemic has stimulated research for an effective treatment and vaccine. For this research to be successful, it is necessary to understand the pathology of the virus. So far, we know that this virus can harm different organs of the body. Although the exact mechanisms are still unknown, this phenomenon may result from the body's secretion of prostaglandin E2 (PGE2), which is involved in several inflammation and immunity pathways. Noticeably, the expression of this molecule can lead to a cytokine storm causing a variety of side effects. In this paper, we discuss those side effects in SARS‐COV‐2 infection separately to determine whether PGE2 is, indeed, an important causative factor. Lastly, we propose a mechanism by which PGE2 production increases in response to COVID‐19 disease and suggest the possible direct relation between PGE2 levels and the severity of this disease. Also see the video abstract here: https://youtu.be/SnPFAcjxxKw.
... Although the mechanisms linking these pathological conditions have not been revealed (Huxtable et al., 2011), it is likely that proinflammatory mediators could affect the generation and control of breathing (Herlenius, 2011;Huxtable et al., 2011). For instance, peripheral application of proinflammatory mediators can modulate respiratory centers (Ericsson et al., 1997;Herlenius, 2011) and reduce breathing in animals (Frøen et al., 2000(Frøen et al., , 2002Guerra et al., 1988;Hofstetter and Herlenius, 2005;Hofstetter et al., 2007;Hutchinson et al., 2008;Kitterman et al., 1983;Olsson et al., 2003;Siljehav et al., 2012;Stoltenberg et al., 1994;Tai and Adamson, 2000) and in humans (Hoch and Bernhard, 2000;Preas et al., 2001). Peripheral infection and inflammation can induce central neuroinflammation (Elmore et al., 2014;Henry et al., 2009;Liu et al., 2012), which is produced by microglia (Elmore et al., 2014;Henry et al., 2009;Liu et al., 2012). ...
... It is possible that microglial activation triggers the release of one or several inhibitory neuromodulators (Henry et al., 2009;Kaur et al., 2013;Lai and Todd 2006;Smith et al., 2013;Yang et al., 2013) that regulate the preB€ otC. Among the neuromodulators released by microglia are several inhibitors of respiratory rhythm generation (Aleksandrova et al., 2015;Gresham et al., 2011;Guerra et al., 1988;Kitterman et al., 1983;Olsson et al., 2003;Tai and Adamson, 2000;VanDam et al., 2008;), such as interleukins (Aleksandrova et al., 2015;Gresham et al., 2011;Henry et al., 2009;Kaur et al., 2013;Lai and Todd 2006;Olsson et al., 2003;Smith et al., 2013;Yang et al., 2013), prostaglandin E2 (Guerra et al., 1988;Kitterman et al., 1983;Tai and Adamson, 2000;Wang et al., 2011;Zhang et al., 2009), hydrogen peroxide (Garcia et al., 2011), adenosine (Lauro et al., 2010;VanDam et al., 2008;Zwicker et al., 2011) and glycine (Hayashi et al., 2006;Ren and Greer, 2006). ...
... It is possible that microglial activation triggers the release of one or several inhibitory neuromodulators (Henry et al., 2009;Kaur et al., 2013;Lai and Todd 2006;Smith et al., 2013;Yang et al., 2013) that regulate the preB€ otC. Among the neuromodulators released by microglia are several inhibitors of respiratory rhythm generation (Aleksandrova et al., 2015;Gresham et al., 2011;Guerra et al., 1988;Kitterman et al., 1983;Olsson et al., 2003;Tai and Adamson, 2000;VanDam et al., 2008;), such as interleukins (Aleksandrova et al., 2015;Gresham et al., 2011;Henry et al., 2009;Kaur et al., 2013;Lai and Todd 2006;Olsson et al., 2003;Smith et al., 2013;Yang et al., 2013), prostaglandin E2 (Guerra et al., 1988;Kitterman et al., 1983;Tai and Adamson, 2000;Wang et al., 2011;Zhang et al., 2009), hydrogen peroxide (Garcia et al., 2011), adenosine (Lauro et al., 2010;VanDam et al., 2008;Zwicker et al., 2011) and glycine (Hayashi et al., 2006;Ren and Greer, 2006). ...
Inflammation has been linked to the induction of apneas and Sudden Infant Death Syndrome, whereas proinflammatory mediators inhibit breathing when applied peripherally or directly into the CNS. Considering that peripheral inflammation can activate microglia in the CNS and that this cell type can directly release all proinflammatory mediators that modulate breathing, it is likely that microglia can modulate breathing generation. It might do so also in hypoxia, since microglia are sensitive to hypoxia, and peripheral proinflammatory conditions affect gasping generation and autoresuscitation. Here, we tested whether microglial activation or inhibition affected respiratory rhythm generation. By measuring breathing as well as the activity of the respiratory rhythm generator (the preBötzinger complex), we found that several microglial activators or inhibitors, applied intracisternally in vivo or in the recording bath in vitro, affect the generation of the respiratory rhythms both in normoxia and hypoxia. Furthermore, microglial activation with lipopolysaccharide affected the ability of the animals to autoresuscitate after hypoxic conditions, an effect that is blocked when lipopolysaccharide is co-applied with the microglial inhibitor minocycline. Moreover, we found that the modulation of respiratory rhythm generation induced in vitro by microglial inhibitors was reproduced by microglial depletion. In conclusion, our data show that microglia can modulate respiratory rhythm generation and autoresuscitation. GLIA 2015.
... 9 Apnea complicates bronchiolitis 5% of the time, but emerges after the clinical appearance of bronchiolitis in just 1%. [8][9][10] The respiratory pauses commonly seen in small infants are terminated by hypercarbic or hypoxic autoresuscitation. Failure of this autoresuscitation leads to central apnea. ...
... Increasing evidence suggests that viral respiratory tract infections trigger this central apnea by increasing prostaglandin E 2 (PGE 2 ) binding of EP3 receptors in the medulla. [10][11][12][13] In immature or otherwise vulnerable infants PGE 2 binding of EP3 receptors appears to induce failure of autoresuscitation; the mature response is fever. 10,14-17 PGE 2 levels rise within 24 hours of RSV infection. ...
... 20,21 The relevance of this pathophysiological model to clinicians is first, central apnea can be expected to occur early in the course of illness when other signs are mild and the infant would be discharged from the ED, and second, the usual clinical sign of elevated PGE 2 (fever) cannot be relied on. 10,16,22,23 PGE 2 levels cannot be measured in the ED so emergency physicians must find other ways to avoid discharging infants who will subsequently have central apnea at home. ...
Background and objectives:
Central apnea complicates, and may be the presenting complaint in, bronchiolitis. Our objective was to prospectively derive candidate clinical decision rules (CDRs) to identify infants in the emergency department (ED) who are at risk for central apnea.
Methods:
We conducted a prospective observational study over 8 years. The primary outcome was central apnea subsequent to the initial ED visit. Infants were enrolled if they presented with central apnea or bronchiolitis. We excluded infants with obstructive apnea, neonatal jaundice, trauma, or suspected sepsis. We developed 3 candidate CDRs by using 3 techniques: (1) Poisson regression clustered on the individual, (2) classification and regression tree analysis (CART), and (3) a random forest (RF).
Results:
We analyzed 990 ED visits for 892 infants. Central apnea subsequently occurred in the hospital in 41 (5%) patients. Parental report of apnea, previous history of apnea, congenital heart disease, birth weight ≤2.5 kg, lower weight, and age ≤6 weeks all identified a group at high risk for subsequent central apnea. All CDRs and RFs were 100% sensitive (95% confidence interval [CI] 91%-100%) and had a negative predictive value of 100% (95% CI 99%-100%) for the subsequent apnea. Specificity ranged from 61% to 65% (95% CI 58%-68%) for CDRs based on Poisson models; 65% to 77% (95% CI 62%-90%) for CART; and 81% to 91% (95% CI 78%-92%) for RF models.
Conclusions:
All candidate CDRs had a negative predictive value of 100% for subsequent central apnea.
... Previous studies that also explored the central effects of prostaglandins on breathing obtained results that are partly different from the data presented here (Hofstetter et al. 2007, Ballanyi et al. 1997, Siljehav et al 2012, Tai et al. 2000. Given the complexity of the modulatory effects caused by prostaglandins such differences may not be surprising, in particular since the other studies employed different approaches and addressed the role of prostaglandins in different contexts. ...
Key points
Prostaglandin E 2 (PGE 2 ) augments distinct inspiratory motor patterns, generated within the preBötzinger complex (preBötC), in a dose‐dependent way. The frequency of sighs and gasping are stimulated at low concentrations, while the frequency of eupnoea increases only at high concentrations.
We used in vivo microinjections into the preBötC and in vitro isolated brainstem slice preparations to investigate the dose‐dependent effects of PGE 2 on the preBötC activity.
Synaptic measurements in whole cell voltage clamp recordings of inspiratory neurons revealed no changes in inhibitory or excitatory synaptic transmission in response to PGE 2 exposure.
In current clamp recordings obtained from inspiratory neurons of the preBötC, we found an increase in the frequency and amplitude of bursting activity in neurons with intrinsic bursting properties after exposure to PGE 2 .
Riluzole, a blocker of the persistent sodium current, abolished the effect of PGE 2 on sigh activity, while flufenamic acid, a blocker of the calcium‐activated non‐selective cation conductance, abolished the effect on eupnoeic activity caused by PGE 2 .
Abstract
Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E 2 (PGE 2 ) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBötzinger complex (preBötC), a medullary area that is critical for breathing. Low concentrations of PGE 2 (100–300 n m ) increased the sigh frequency, while higher concentrations (1–2 μ m ) were required to increase the eupnoeic frequency. The concentration‐dependent effects were similarly observed in the isolated preBötC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current ( I Nap ), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium‐activated non‐selective cation conductance ( I CAN ) abolished the effect of PGE 2 on fictive eupnoea at higher concentrations. At the cellular level PGE 2 significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE 2 affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE 2 differentially modulates sigh, gasping and eupnoeic activity by differentially increasing I Nap and I CAN currents in preBötC neurons.
... Following induction of COX-2 and mPGES-1 activity by proinflammatory stimuli such as IL-1, PGE 2 is released into the brain parenchyma (11) and mediates several central effects including fever (5), pain (28), anorexia (12), and respiratory depression (51). PGE 2 depresses breathing in fetal and newborn sheep, mice, and in humans in vivo (25,30,51), and also inhibits respiration-related neurons in vitro (23,25,39). ...
... Following induction of COX-2 and mPGES-1 activity by proinflammatory stimuli such as IL-1, PGE 2 is released into the brain parenchyma (11) and mediates several central effects including fever (5), pain (28), anorexia (12), and respiratory depression (51). PGE 2 depresses breathing in fetal and newborn sheep, mice, and in humans in vivo (25,30,51), and also inhibits respiration-related neurons in vitro (23,25,39). Others and we have suggested that PGE 2 serves as a critical mediator of inflammation and apnea (22,24,25,48). ...
Prostaglandin E2 (PGE2) serves as a critical mediator of hypoxia, infection and apnea in term and preterm babies. We hypothesized that the Prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1beta (i.p) attenuated the hypercapnic response in WT but not in neonatal (P9) EP3R-/- mice (P < 0.05). The hypercapnic responses in brainstem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R-/- preparations (P < 0.05). After severe hypoxic exposure in vivo, IL-1beta prolonged time to autoresuscitation after anoxic exposure in WT but not in EP3R-/- mice. Moreover, during severe hypoxic stress EP3R-/- mice had an increased gasping duration (P < 0.01) as well as number of gasps (P < 0.01), irrespective of i.p treatment, compared to WT mice. Furthermore, EP3R-/- mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia (P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R-/- mice (P < 0.05). In vitro, EP3R-/- brainstem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium (P < 0.05). In conclusion, PGE2 exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates.
... Prostaglandin synthesis inhibitors, which block endogenous prostaglandin production, increase breathing movements and central respiration during early postnatal life (12,14). During the perinatal period, endogenous PGE 2 has a tonic effect on respiratory rhythmogenesis and breathing (8). ...
... During the perinatal period, endogenous PGE 2 has a tonic effect on respiratory rhythmogenesis and breathing (8). Moreover, during periods of vulnerability, newborns may be at risk of hypoventilation and/or apneas in response to pathophysiological events that increase central PGE 2 (1,12). Thus, should nonsteroidal anti-inflammatory drugs or more specific mPGES-1 inhibitors or EP3R antagonists be administered to all vulnerable infants in the neonatal intensive care units to potentially improve respiratory outcomes? ...
Background:
Apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin E2 (PGE2) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGE synthase-1 (mPGES-1) PGE2 pathway influences respiratory control and response to hypoxia.
Methods:
Nine-d-old wild-type (WT) mice, mPGES-1 heterozygote (mPGES-1+/–), and mPGES-1 knockout (mPGES-1–/–) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1β (IL-1β) (10 µg/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp).
Results:
IL-1β worsened survival in WT mice but not in mice with reduced or no mPGES-1. Reduced expression of mPGES-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGE2 was not dependent on mPGES-1 expression.
Conclusion:
Activation of mPGES-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. Attenuation of mPGES-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. Consequently, inhibition of the mPGES-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders.
... Indomethacin, a non-specific COX inhibitor, attenuates the respiratory depression induced by IL-l (Olsson et al., 2003). PGE 2 itself depresses breathing in fetal and newborn sheep in vivo (Guerra et al., 1988;Kitterman et al., 1983;Tai and Adamson, 2000) and inhibits respiration-related neurons in vitro (Olsson et al., 2003). To further investigate the effects of IL-l on breathing in neonates we used 9-day-old wildtype mice and examined their response to changes in ambient CO 2 and O 2 90 min after IL-1-administration. IL-1 reduced breathing during normoxia but not temperature or peripheral chemoreceptors when examined after 90 min. ...
Infection in infancy may dramatically aggravate an underlying cardiorespiratory dysfunction during a susceptible postnatal period. Children with immature brainstem respiratory control, as well as infants, may have periodic irregular breathing with potential detrimental apneas that are increased during sleep as well as during infectious episodes. Data now indicate that the proinflammatory cytokine interleukin (IL)-1β impairs respiration during infection via prostaglandin E2 (PGE(2)) and that infection, with associated eicosanoid release, is one of the main causes of respiratory disorders in preterm infants. Moreover, brainstem microsomal prostaglandin E synthase-1 (mPGES-1) is rapidly activated during transient hypoxia. An inflammatory mediated activation of the mPGES-1 pathway, e.g., by viral or bacterial infection, rapidly induces release of PGE(2) in the vicinity of brainstem cardio-respiratory-related centers. This will depress the autonomic control networks, including the central drive to breathe. Hypoxia may then further reduce the activity of vital brainstem centers and the ability to autoresuscitate. This might have fatal consequences in vulnerable infants during a susceptible time frame. Here the evidence from human, animal and molecular studies to support this hypothesis is reviewed and how the pathogenesis of apnea and the response to hypoxia is associated with inflammatory pathways is discussed.
... Depending on the EP receptors present in organs or tissues, PGE 2 can affect diverse biological functions including inflammatory responses (Brigham et al., 1988;Downey et al., 1988;Wakabayashi et al., 2002;Goulet et al., 2004), platelet aggregation (Fabre et al., 2001;Gross et al., 2007); febrile responses to LPS (Ivanov et al., 2002(Ivanov et al., , 2003Ivanov and Romanovsky, 2004;Li et al., 2006); airway tone and respiratory function (Brigham et al., 1988;Guerra et al., 1988;Savich et al., 1995;Hartney et al., 2006;Tilley et al., 2003), cardiac function (Hintze and Kaley, 1984;Panzenbeck et al., 1989;Klein et al., 2004), and systemic and regional (renal, pulmonary) blood pressure and flow (Cassin et al., 1979;Lock et al., 1980;Downey et al., 1988;Guerra et al., 1988;Audoly et al., 1999;Tod et al., 1992;Gao et al., 1996). The responses elicited by PGE 2 can vary dramatically depending on the pre-or postnatal stage of development and maturation (Tai and Adamson, 2000). ...
... The respiratory inhibition elicited by PGE 2 in 45-to 55-d-old broilers resembles the responses elicited by PGE 2 in fetal and neonatal mammals. Prostaglandin E 2 profoundly reduces spontaneous breathing movements in fetal mammals and reduces the RR, tidal volume, and blood oxygenation in neonatal mammals (Kitterman et al., 1983;Murai et al., 1987;Guerra et al., 1988;Savich et al., 1995;Tai and Adamson, 2000;Hofstetter et al., 2007). The hypoventilation induced by PGE 2 does not consistently involve peripheral chemoreceptors (carotid and aortic bodies) but instead is mediated primarily through receptors located within the central nervous system (Murai et al., 1987;Guerra et al., 1988;Tai and Adamson, 2000;Hofstetter et al., 2007). ...
... Prostaglandin E 2 profoundly reduces spontaneous breathing movements in fetal mammals and reduces the RR, tidal volume, and blood oxygenation in neonatal mammals (Kitterman et al., 1983;Murai et al., 1987;Guerra et al., 1988;Savich et al., 1995;Tai and Adamson, 2000;Hofstetter et al., 2007). The hypoventilation induced by PGE 2 does not consistently involve peripheral chemoreceptors (carotid and aortic bodies) but instead is mediated primarily through receptors located within the central nervous system (Murai et al., 1987;Guerra et al., 1988;Tai and Adamson, 2000;Hofstetter et al., 2007). Hypoventilatory responses to PGE 2 tend to wane as neonatal mammals mature (Tai and Adamson, 2000). ...
Prostaglandin E2 (PGE2) affects pulmonary arterial pressure (PAP), pulmonary vascular resistance (PVR), and respiratory rate (RR) in mammals, but
no information previously was available regarding avian pulmonary responses to PGE2. Two experiments were conducted in which 45- to 55-d-old male broiler chickens were infused i.v. with PGE2 at the lowest rate (30 μg/min for 4 min) that reliably reduced PAP during pilot studies. When compared with preinfusion (control)
values in experiment 1, PGE2 reduced PAP from 19 ± 1 to 16 ± 1 mmHg (P < 0.001) and reduced mean systemic arterial pressure from 111 ± 6 to 81 ± 5 mmHg (P < 0.001) but did not significantly reduce heart rate (HR; control: 338 ± 9 beats/min; PGE2: 320 ± 12 beats/min; P > 0.05). Infusing PGE2 also reduced the RR from 57 ± 2 to 46 ± 4 breaths/min (P < 0.001) and reduced the percentage saturation of hemoglobin with oxygen (%HbO2) from 85 ± 2 to 77 ± 3%HbO2 (P < 0.001). After the PGE2 infusion ceased, the PAP, mean systemic arterial pressure, RR, and %HbO2 recovered within 8 min to levels that did not differ from preinfusion control values. In experiment 2, an ultrasonic flow
probe was surgically implanted on 1 pulmonary artery to measure cardiac output (CO). When compared with preinfusion control
values, PGE2 reduced CO from 140 ± 6 to 111 ± 5 mL/kg of BW × min (P < 0.001), reduced PAP from 25 ± 2 to 21 ± 1 mmHg (P < 0.001), and reduced RR from 49 ± 4 to 35 ± 4 breaths/min (P < 0.001). The reduction in CO was caused by a reduction in HR from 305 ± 9 to 260 ± 9 beats/min without a significant reduction
in stroke volume (control: 0.46 ± 0.02 mL/kg of BW × beat; PGE2: 0.43 ± 0.02 mL/kg of BW × beat; P = 0.158). After the PGE2 infusion ceased the CO, PAP, RR, and HR recovered within 9 min to levels that did not differ from preinfusion control values.
The PVR, calculated as PAP/CO, was not altered by PGE2 (control: 0.18 ± 0.01 relative resistance units; PGE2: 0.20 ± 0.02 relative resistance units; P > 0.723). These results indicate that in broilers PGE2 reduced PAP by reducing CO rather than by acting as a pulmonary vasodilator to lower PVR. The PGE2-induced reductions in PAP would benefit broilers that are susceptible to pulmonary hypertension syndrome by reducing their
right ventricular overload; however, the reductions in CO and RR combined with the onset of systemic arterial hypoxemia would
accelerate the pathophysiological progression leading to terminal pulmonary hypertension syndrome.
