Bacterial chondronecrosis with osteomyelitis and lameness in broilers: a review.

This review focuses on a specific cause of lameness known as bacterial chondronecrosis with osteomyelitis (BCO) in broilers. Rapid increases in body weight impose excessive torque and shear stress on structurally immature epiphyseal and physeal cartilage, primarily in the proximal femora, proximal tibiae, and flexible thoracic vertebrae. Excessive mechanical stress creates osteochondrotic clefts among the chondrocytes of susceptible growth plates. These wound sites are colonized by hematogenously distributed opportunistic bacteria, culminating in the gross abscesses and necrotic voids that are pathognomonic for terminal BCO. Lameness attributable to characteristic BCO lesions can be reproduced by rearing broilers on wire flooring to create persistent footing instability and physiological stress, without the need to inoculate the birds with pathogenic bacteria that presumably are present but quiescent within the bird's microbial communities or in the environment. Experiments using the wire-flooring model revealed innate differences in the susceptibility of broiler lines to BCO, and demonstrated that BCO incidences can be reduced by prophylactically providing probiotics in the feed, by prophylactically adding 25-hydroxy vitamin D3 to the drinking water, or by therapeutically adding the antibiotic enrofloxacin to the drinking water. Hatchery and chick quality issues clearly influence the susceptibility of broilers to BCO. When broilers remain in a sitting posture for prolonged periods, the major arteries supplying their legs may be compressed. These episodes of inadequate blood flow may prevent chondrocyte maturation and trigger focal necrosis, thereby making the epiphyseal and physeal cartilage highly susceptible to osteochondrosis and BCO. Much remains to be revealed regarding the pathogenesis of BCO. Further revelations will be facilitated by the availability of the now-validated wire-flooring models that consistently trigger high incidences of BCO in experimental flocks.

A quantitative trait locus for ascites on chromosome 9 in broiler chicken lines.

A genome-wide SNP survey was used to identify chromosomal regions that showed linkage disequilibrium with respect to ascites susceptibility and ventricular hypertrophy in an F2 cross between previously described ascites-resistant and -susceptible lines. Variable number tandem repeats were used to obtain genotype data to further characterize these regions. A region on chromosome 9 (12 to 13 Mbp in 2011 assembly) shows association with ascites in the ascites lines and in several commercial broiler breeder lines with a significant sex effect. There are 2 candidate genes, AGTR1 (an angiotensin II type 1 receptor) and UTS2D (urotensin 2 domain containing), in this region that have been associated with hypertension and hypoxic response in mammals.

Immunohistochemical examination of plexiform-like complex vascular lesions in the lungs of broiler chickens selected for susceptibility to idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, and by extensive vascular remodelling. In human IPAH patients, remodelling of the pulmonary vasculature results in the formation of plexiform lesions in the terminal pulmonary arterioles. Various molecules are expressed in the human plexiform lesions, including alpha smooth muscle actin, von Willebrand factor, vascular endothelial growth factor, vascular endothelial growth factor receptor type 2, hypoxia inducible factor-1α, survivin, tenascin, collagen, fibronectin, and various immune/inflammatory cells such as, cytotoxic lymphocytes, B lymphocytes, MHC class II cells, and monocytes/macrophages are also present. Plexiform lesions rarely develop in the lungs of laboratory animals, but plexiform-like complex vascular lesions (CVL) do develop spontaneously in the lungs of broiler chickens from an IPAH-susceptible line. To examine angioproliferative and immune-system-related activities associated with CVL in broiler lungs, paraformaldehyde-fixed, paraffin-embedded lung sections from 8-week-old to 24-week-old broiler chickens were stained immunohistochemically using monoclonal or polyclonal antibodies specific for angioproliferative molecules and immune/inflammatory cells. The CVL in the lungs of broiler chickens exhibited positive staining for both angioproliferative molecules and immune/inflammatory cells. These observations combined with the close histological resemblance of broiler CVL to the plexiform lesions of human IPAH patients further validates chickens from our IPAH-susceptible line as an excellent animal model of spontaneous plexogenic arteriopathy.

Impact of experimentally induced bacterial chondronecrosis with osteomyelitis (BCO) lameness on health, stress, and leg health parameters in broilers.

Stress and lameness negatively affect the health, production, and welfare of broilers. Bacterial chondronecrosis with osteomyelitis (BCO) is a leading cause of stress and lameness in commercial broilers. External changes in skin temperature related to changes in blood flow can be detected with infrared thermography (IRT), offering a noninvasive tool to assess the health of animals. This study compared physiological and noninvasive measures of stress and lameness in clinically healthy and lame male broiler chickens between 25 and 56 d. Birds were raised in pens within separate environmental chambers containing either litter flooring (sound) or wire flooring, with the latter established to induce BCO lameness (lame). Physiological and noninvasive measures of stress and lameness were collected: body weight, (BW), relative bursa weight, core body temperature, corticosterone (CORT) concentrations in serum and feathers, surface temperatures of the head (eye and beak) and leg (hock, shank, and foot) regions by infrared thermography (IRT), leg blood oxygen saturation (leg O2), and BCO lesion severity scores of tibial head necrosis (THN) and femoral head necrosis (FHN). Lame birds exhibited greater FHN and THN lesion severities, core body temperatures, and serum CORT (P < 0.05), but had lower BW, relative bursa weight, leg O2, and IRT surface temperatures of the beak, hock, shank, and foot compared with sound birds (P < 0.05). The difference in THN lesion severity between sound and lame birds decreased with age. Linear relationships between leg O2 with IRT leg surface temperatures were positive and negative between leg O2 with BCO lesion severity (P < 0.05). There were negative correlations between serum CORT with hock, shank and foot temperatures (P < 0.001), indicating that BCO is stressful. These results indicate that birds lame from BCO are stressed, have reduced oxygen saturation of blood in their legs, and that IRT surface temperatures can be used as noninvasive indicators of stress and lameness in broilers.

Differential expression of vasoactive mediators in microparticle-challenged lungs of chickens that differ in susceptibility to pulmonary arterial hypertension.

Pulmonary hypertension syndrome (PHS; ascites) in fast growing meat-type chickens (broilers) is characterized by the onset of idiopathic pulmonary arterial hypertension (IPAH) leading to right-sided congestive heart failure and terminal ascites. Intravenous microparticle (MP) injection is a tool used by poultry geneticists to screen for the broilers that are resistant (RES) or susceptible (SUS) to IPAH in a breeding population. MPs occlude pulmonary arterioles and initiate focal inflammation, causing local tissues and responding leukocytes to release vasoactive mediators such as serotonin (5-HT), endothelin-1 (ET-1), and nitric oxide (NO). RT-PCR was used to examine the differences between RES and SUS broilers in terms of gene expression of ET-1, ET receptor types A and B (ET(A) and ET(B)), the serotonin transporter (SERT), serotonin receptors (5-HT(1A), 5-HT(2A), 5-HT(1B), 5-HT(2B)), endothelial NO synthase (eNOS), and inducible NOS (iNOS) in the lungs of these broilers before (0 h) and after (2, 6, 12, 24, and 48 h) MP injection. In SUS broilers MP injection elicited higher (P < 0.05) pulmonary expression of 5-HT(1A), 5-HT(2B), and ET-1, which promote vasoconstriction and proliferation of pulmonary arterial smooth muscle cells (PASMC). In RES broilers the MP injection elicited higher expression of eNOS, iNOS, and ET(B), which promote vasodilation and inhibit PASMC proliferation. These observations support the hypothesis that the resistance of broiler chickens to IPAH may be due to the higher expression of vasoactive mediators that favor enhanced vasodilation and attenuated vasoconstriction during MP injection challenges to the pulmonary vasculature.

Microbiota Analysis of Chickens Raised Under Stressed Conditions.

A substantial progress has been made toward understanding stress-associated gut and extraintestinal microbiota. However, a comprehensive understanding of the extraintestinal microbiota of chickens raised under stressed conditions is lacking. In this study, chickens were raised on a wire-floor model to induce stress, and the microbiota in the gut (ceca) and extraintestinal sites (blood, femur, and tibia) were characterized at different ages (1, 17, and 56 days) using 16S rRNA gene microbiota profiling. Open reference OTU picking showed extraintestinal sites had a significantly higher number of unassigned OTUs compared to ceca across all ages of chickens. Extraintestinal sites of all ages, irrespective of body sites, as well as ceca of 1 day-old chickens had significantly lower alpha diversity than ceca of older chickens. Intriguingly, bacterial diversity (alpha and beta) and OTU interaction network analysis showed relatively stable bacterial composition within the extraintestinal sites of chickens regardless of age and sites compared to ceca. Furthermore, assessment using UniFrac distance suggested the gut as a possible source of extraintestinal bacteria. Lastly, LEfSe analysis showed that both commensal and pathogenic bacteria were translocated into the extraintestinal tissues and organs under the stress. Extraintestinal sites have highly abundant novel taxa that need to be further explored. In ovo microbiota colonization and/or translocation of circulating maternal blood microbiota into ovarian follicles might be the source of intestinal and extraintestinal microbiota in 1 day-old chickens. Our comprehensive microbiota data including extraintestinal sites in reference to gut provide unique insights into microbiota of chickens raised under stressed conditions, which may be relevant in other animal species as well.

Chondronecrosis with osteomyelitis in broilers: further defining a bacterial challenge model using standard litter flooring and protection with probiotics.

This report demonstrates that high levels of lameness can be induced by a limited bacterial challenge in drinking water for birds raised on litter flooring, comparable with lameness induced by the gold standard for inducing lameness, growth on suspended wire flooring. The bacterium used in the challenge was cultured from lesions in birds induced for bacterial chondronecrosis with osteomyelitis (BCO) in the wire-flooring model so the epidemiology appears similar. The litter-flooring model could better approximate broiler operations. Furthermore, the work demonstrates that 2 commercial probiotics (GalliProTect and GalliProMax) can reduce lameness in the bacterial challenge litter-flooring model. Lameness attributable to BCO is one of the most significant animal welfare issues for broiler production. The wire-flooring and litter-flooring models afford alternatives for understanding the etiology, and epidemiology of BCO, and development of management strategies to reduce lameness. Probiotics afford a promising management strategy. The results suggest that the probiotic protection may extend beyond just intestinal health and intestinal barrier function.

Broiler stress responses to light intensity, flooring type, and leg weakness as assessed by heterophil-to-lymphocyte ratios, serum corticosterone, infrared thermography, and latency to lie.

Stress and leg weakness are detrimental to broiler production, health, and welfare. Traditional methods to evaluate stress may be stressful to the bird because they are invasive and require handling and restraint. Two studies examined the effects of light intensity and flooring on the following in broilers: 1) traditional methods for assessing stress using heterophil-to-lymphocyte ratios and serum corticosterone (CORT) concentrations, 2) noninvasive measures of stress from infrared thermography (IRT) eye and beak surface temperatures, and 3) latency-to-lie (LTL) test times of birds tested individually and in groups of 5. Day-of-hatch male broiler chicks were placed into 6 pens (N = 120 chicks/pen). At 1 wk, pens were allocated to 3 light intensity treatments (2, 5, or 10 lux). At 4 wk, half of the birds from each pen were moved to a pen with wire flooring and the same light intensity. At 1, 4, 5, and 8 wk, blood samples were collected and IRT images of the heads of 5 clinically healthy broilers from each pen were captured. In study 2, IRT images of the heads of birds that became lame in the wire flooring pens were taken. There were no treatment effects on the LTL times of birds tested in groups or individually (P > 0.05). On day 56 in study 1, birds on wire flooring had elevated heterophil-to-lymphocyte ratios and CORT concentrations (P ≤ 0.002) and depressed IRT eye and beak temperatures (P < 0.0001). In both studies, there were negative correlations between CORT concentrations and IRT beak surface temperatures (P < 0.05). Lame birds had lower IRT eye and beak surface temperatures than sound birds (P ≤ 0.004), and the IRT beak surface temperatures of lame birds were lower than their eye surface temperatures (P = 0.004) in study 2. These studies indicate that the IRT surface temperatures of the eye, and more distinctly of the beak, can be used as sensitive noninvasive indicators of stress.

Chondronecrosis with osteomyelitis in broilers: further defining lameness-inducing models with wire or litter flooring to evaluate protection with organic trace minerals.

The feed additive Availa-ZMC was investigated for the ability to reduce lameness in broilers using 2 alternative models for inducing lameness. The mixture of organic trace minerals was effective in reducing lameness by 20% in the wire flooring model and 25% in the litter flooring model with the bacterial challenge. Lameness in both models is overwhelmingly attributable to bacterial chondronecrosis with osteomyelitis. The reduction in lameness was associated, at least in part, with enhanced intestinal barrier integrity mediated by elevated expression of tight junction proteins and stimulation of bactericidal killing of adherent peripheral blood monocytes obtained from the birds treated with Availa-ZMC. Lameness is a major animal welfare concern in broiler production. The wire flooring model and litter flooring model with the bacterial challenge are effective models for evaluation of management strategies for mitigating infectious causes of lameness.

Upregulation of SERT and ADORA1 in broilers with acute right ventricular failure.

Pulmonary hypertension (PH), remains a challenging disease with a large impact on both humans and meat-type chickens. PH is characterized by the onset of idiopathic pulmonary arterial hypertension leading to right ventricular failure. In this experiment relative gene expression of adenosine A1 receptor (ADORA1), serotonin transporter (SERT), phosphodiesterase 5A (PDE5) and troponin T2 were compared in hearts from broilers with acute right ventricular failure and from healthy birds. There were major increases in adenosine A1 receptor (177%) and serotonin transporter (475%), and more modest but significant increases in PDE5 (146%) and troponin T2 (140%) gene expressions in broilers with right ventricular failure compared to healthy birds (P<0.01). This novel report shows that pulmonary hypertension related gene expression in broilers is similar to that in humans. This molecular similarity between PH in broilers and human patients suggests, first, that they will make a suitable animal model for study PH in humans, but also that the literature on PH in humans may be profitably applied to the study of PH in broilers.

The utility of infrared thermography for evaluating lameness attributable to bacterial chondronecrosis with osteomyelitis.

Bacterial chondronecrosis with osteomyelitis (BCO) is a leading cause of lameness in broilers. Infrared thermography (IRT) is a noninvasive technique for measuring infrared radiation from an object and can be used to evaluate clinical health. Two replicated studies compared the effect of light intensity on broilers grown on a wire flooring model that experimentally increased their susceptibility to and incidence of BCO lameness. Day-of-hatch male broiler chickens were placed into 6 pens on wood shavings litter, and at 1 wk one of 3 light intensity treatments (2, 5, or 10 lux) was allotted. At 4 wk half of the population from each pen was moved to a pen with wire flooring and the same light intensity. At 1, 4, 5, and 8 wk, an IRT image of the legs of 5 clinically healthy broilers from each pen was taken. The right and left proximal femora and tibiae of sound and lame broilers were scored for femoral head necrosis (FHN) and tibial head necrosis (THN) lesion severity. There were minimal effects of light intensity and flooring. In Study 1, but not Study 2, broilers on wire flooring weighed less on day 38 (P = 0.007) and days 57 to 58 (P = 0.003) compared to those on litter. The proportion of broilers that became lame on wire flooring was 52% in Study 1 and 14% in Study 2. The proportion of sound broilers from litter and wire flooring pens with subclinical signs of BCO in their right or left proximal growth plates was over 45% for FHN and 92% for THN, and lame broilers had more severe (P < 0.0001) FHN and THN compared to sound broilers. IRT surface temperatures of the hock joint, shank, and foot were consistently lower (P < 0.0001) in broilers that became lame when compared to sound. Therefore, IRT surface temperatures of broiler leg regions may be useful for detecting lesions attributed to BCO.

An evaluation of methods for measuring stress in broiler chickens.

There are potential advantages for using noninvasive methods instead of conventional approaches for measuring corticosterone (CORT) as a metric of stress. Two studies compared blood heterophil: lymphocyte (H:L) ratios, serum CORT, cecal content CORT (Study 1), colon content CORT (Study 2), and feather CORT concentrations for broiler chicks receiving drinking water with or without added CORT. On day 28, male broilers (N = 140) were provided tap water (Control group) or water containing 20 mg/L of CORT (CORT group) for up to 72 h. Body weight (BW), blood, feather, cecal, and colon content samples were collected from 10 birds from each treatment group at 0, 6, 12, 24, 30, 48, and 72 h. Data were analyzed with a JMP Pro ANOVA. Mean comparisons were analyzed on significant treatment effects using post hoc t-tests to compare control and CORT measures within each sampling time point. Pearson's pairwise correlations for all data were performed. A treatment by time interaction affected all measures in both studies. In both studies, CORT treatment reduced body weight and increased H:L ratios at later time points. In study 1 cecal content CORT concentrations were elevated with CORT treatment after 24 h, whereas in study 2 colon content CORT concentrations were elevated after 6 h. CORT treatment increased body and primary feather CORT and primary feather CORT increased with time in control groups in both studies. Serum CORT exhibited the lowest variability compared with all other sample sources used for determining CORT. Estimates of CORT by different methods were positively correlated. These results indicate that serum CORT concentrations most reliably reflect the CORT status of broilers, and that feather CORT concentrations demonstrated potential for estimating stress in broilers.

Chondronecrosis with osteomyelitis in broilers: Further defining a bacterial challenge model using the wire flooring model.

Lameness in broiler chickens is a significant animal welfare and financial issue. Bacterial chondronecrosis with osteomyelitis (BCO) leading to lameness can be enhanced by rearing young broilers on wire flooring. Using the wire floor system, we identified Staphylococcus agnetis as the predominant isolate in BCO of the proximal tibiae and femora, and blood of lame broilers. Administration of S. agnetis isolates in water can induce lameness. We now report that the wire floor system increases bacterial translocation into the blood stream. We have also determined that approximately 105 CFU/mL is the minimum effective dose in the drinking water and that challenge at 10, 20, or 30 days of age produces similar incidences of lameness. BCO isolates of S. agnetis are much more effective than other Staphylococcus species and can overwhelm the protective effects of some commercial probiotics. Finally, we also demonstrated that the BCO lameness induced by administration of S. agnetis in the drinking water is transmissible to unchallenged broilers in the same pen.

An investigation into blood microbiota and its potential association with Bacterial Chondronecrosis with Osteomyelitis (BCO) in Broilers.

Bacterial chondronecrosis with osteomyelitis (BCO) is a common cause of lameness in commercial broiler chickens worldwide. BCO represents substantial production loss and welfare issues of chickens. The bacterial species or communities underlying BCO pathogenesis still remain to be fully characterized. To gain insights on blood microbiota in broilers and its potential association with BCO, blood samples collected from healthy (n = 240) and lame (n = 12) chickens were analyzed by deep sequencing of 16S RNA genes. The chicken blood microbiota were dominated by Proteobacteria (60.58% ± 0.65) followed by Bactroidetes (13.99% ± 0.29), Firmicutes (11.45% ± 0.51), Actinobacteria (10.21% ± 0.37) and Cyanobacteria (1.96% ± 0.21) that constituted 98.18% (± 0.22) of the whole phyla. The bacterial communities consist of 30-40 OTUs in the blood of broiler chickens, regardless of ages and other environmental or host conditions, and the blood microbiomes of BCO chickens were largely distinct from those of healthy chickens. In addition, Linear discriminant analysis (LDA) effect size (LEfSe) method revealed that Staphylococcus, Granulicatella, and Microbacterium were significantly enriched in BCO chickens as compared to healthy chickens. The results from this study have significant implications in understanding blood microbiota present in broiler chickens and its potential role in BCO pathogenesis.

Molecular survey of bacterial communities associated with bacterial chondronecrosis with osteomyelitis (BCO) in broilers.

Bacterial chondronecrosis with osteomyelitis (BCO) is recognized as an important cause of lameness in commercial broiler chickens (meat-type chickens). Relatively little is known about the microbial communities associated with BCO. This study was conducted to increase our understanding of the microbial factors associated with BCO using a culture-independent approach. Using Illumina sequencing of the hyper-variable region V6 in the 16S rRNA gene, we characterized the bacterial communities in 97 femoral or tibial heads from normal and lame broilers carefully selected to represent diverse variations in age, line, lesion type, floor type, clinical status and bone type. Our in-depth survey based on 14 million assembled sequence reads revealed that complex bacterial communities exist in all samples, including macroscopically normal bones from clinically healthy birds. Overall, Proteobacteria (mean 90.9%) comprised the most common phylum, followed by Firmicutes (6.1%) and Actinobacteria (2.6%), accounting for more than 99% of all reads. Statistical analyses demonstrated that there are differences in bacterial communities in different types of bones (femur vs. tibia), lesion types (macroscopically normal femora or tibiae vs. those with pathognomonic BCO lesions), and among individual birds. This analysis also showed that BCO samples overrepresented genera Staphylococcus, whose species have been frequently isolated in BCO samples in previous studies. Rarefaction analysis demonstrated the general tendency that increased severities of BCO lesions were associated with reduced species diversity in both femoral and tibial samples when compared to macroscopically normal samples. These observations suggest that certain bacterial subgroups are preferentially selected in association with the development of BCO lesions. Understanding the microbial species associated with BCO will identify opportunities for understanding and modulating the pathogenesis of this form of lameness in broilers.

Genome Analysis of Staphylococcus agnetis, an Agent of Lameness in Broiler Chickens.

Lameness in broiler chickens is a significant animal welfare and financial issue. Lameness can be enhanced by rearing young broilers on wire flooring. We have identified Staphylococcus agnetis as significantly involved in bacterial chondronecrosis with osteomyelitis (BCO) in proximal tibia and femorae, leading to lameness in broiler chickens in the wire floor system. Administration of S. agnetis in water induces lameness. Previously reported in some cases of cattle mastitis, this is the first report of this poorly described pathogen in chickens. We used long and short read next generation sequencing to assemble single finished contigs for the genome and a large plasmid from the chicken pathogen. Comparison of the S. agnetis genome to those of other pathogenic Staphylococci shows that S.agnetis contains a distinct repertoire of virulence determinants. Additionally, the S. agnetis genome has several regions that differ substantially from the genomes of other pathogenic Staphylococci. Comparison of our finished genome to a recent draft genome for a cattle mastitis isolate suggests that future investigations focus on the evolutionary epidemiology of this emerging pathogen of domestic animals.

Bone circulatory disturbances in the development of spontaneous bacterial chondronecrosis with osteomyelitis: a translational model for the pathogenesis of femoral head necrosis.

This review provides a comprehensive overview of the vascularization of the avian growth plate and its subsequent role in the pathogenesis of bacterial chondronecrosis with osteomyelitis (BCO, femoral head necrosis). BCO sporadically causes high incidences of lameness in rapidly growing broiler (meat-type) chickens. BCO is believed to be initiated by micro-trauma to poorly mineralized columns of cartilage cells in the proximal growth plates of the leg bones, followed by colonization by hematogenously distributed opportunistic bacteria. Inadequate blood flow to the growth plate, vascular occlusion, and structural limitations of the microvasculature all have been implicated in the pathogenesis of BCO. Treatment strategies have been difficult to investigate because under normal conditions the incidence of BCO typically is low and sporadic. Rearing broilers on wire flooring triggers the spontaneous development of high incidences of lameness attributable to pathognomonic BCO lesions. Wire flooring imposes persistent footing instability and is thought to accelerate the development of BCO by amplifying the torque and shear stress imposed on susceptible leg joints. Wire flooring per se also constitutes a significant chronic stressor that promotes bacterial proliferation attributed to stress-mediated immunosuppression. Indeed, dexamethasone-mediated immunosuppression causes broilers to develop lameness primarily associated with avascular necrosis and BCO. Prophylactic probiotic administration consistently reduces the incidence of lameness in broilers reared on wire flooring, presumably by reducing bacterial translocation from the gastrointestinal tract that likely contributes to hematogenous infection of the leg bones. The pathogenesis of BCO in broilers is directly relevant to osteomyelitis in growing children, as well as to avascular femoral head necrosis in adults. Our new model for reliably triggering spontaneous osteomyelitis in large numbers of animals represents an important opportunity to conduct translational research focused on developing effective prophylactic and therapeutic treatments.

Idiopathic pulmonary arterial hypertension: an avian model for plexogenic arteriopathy and serotonergic vasoconstriction.

Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance attributable to vasoconstriction and vascular remodeling of small pulmonary arteries. Vascular remodeling includes hypertrophy and hyperplasia of smooth muscle (medial hypertrophy) accompanied in up to 80% of the cases by the formation of occlusive plexiform lesions (plexogenic arteriopathy). Patients tend to be unresponsive to vasodilator therapy and have a poor prognosis for survival when plexogenic arteriopathy progressively obstructs their pulmonary arteries. Research is needed to understand and treat plexogenic arteriopathy, but advances have been hindered by the absence of spontaneously developing lesions in existing laboratory animal models. Young domestic fowl bred for meat production (broiler chickens, broilers) spontaneously develop IPAH accompanied by semi-occlusive endothelial proliferation that progresses into fully developed plexiform lesions. Plexiform lesions develop in both female and male broilers, and lesion incidences (lung sections with lesions/lung sections examined) averaged approximately 40% in 8 to 52 week old birds. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries, and were associated with perivascular mononuclear cell infiltrates. Serotonin (5-hydroxytryptamine, 5-HT) is a potent vasoconstrictor and mitogen known to stimulate vascular endothelial and smooth muscle cell proliferation. Serotonin has been directly linked to the pathogenesis of IPAH in humans, including IPAH linked to serotonergic anorexigens that trigger the formation of plexiform lesions indistinguishable from those observed in primary IPAH triggered by other causes. Serotonin also plays a major role in the susceptibility of broilers to IPAH. This avian model of spontaneous IPAH constitutes a new animal model for biomedical research focused on the pathogenesis of IPAH and plexogenic arteriopathy.

Plexiform lesions in the lungs of domestic fowl selected for susceptibility to pulmonary arterial hypertension: incidence and histology.

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.