The Presence of Systemic Disease
The presence of systemic disease in dogs with chronic periodontal disease has been suggested as an co-factor in various other diseases, particularly respiratory disease, cardiac disease, atherosclerosis, hepatic disease, renal disease and low birth weight.1,2,3 In most cases there is as yet no conclusive proof of a direct link, but there are multiple plausible explanations for such links.4 Frequent bouts of bacteraemia and endotoxaemia occur due to minor trauma at sites of periodontal inflammation. Those bacteria that survive within the circulation may cause infection or stimulate inflammation and disease at distant sites. Any individuals with defective defense mechanisms are likely to be predisposed to distant and systemic effects of periodontal disease due to increased invasion by micro-organisms and both more severe bacteraemia and greater local production of cytokines.5
Respiratory Disease
Bacteria from the oral cavity may cause respiratory infection on many different ways.6 The most common is aspiration of saliva containing pathogenic bacteria from oral cavity to the lungs. Periodontal pathogens release enzymes and other factors that promote tissue adhesion and invasion both in the oral cavity and at other sites such as respiratory epithelia. Cytokines that are released in inflammation process in the oral cavity enter the systemic circulation and affect distant sites, including the respiratory epithelium which is altered to become more susceptible to establishment of infection and its progression. Periodontal pathogenic bacteria cause the release of cytokines IL-1,IL-6,IL-8 and TNF-α from the tissues of the respiratory tract, particularly endothelial and connective tissue cells7. These proinflammatory cytokines attract inflammatory cells and activate neutrophils, which tend to degranulate causing further tissue damage.
Respiratory diseases and chronic obstructive pulmonary disease are quite common in dogs. The numbers of organisms involved in periodontal disease is phenomenal so the likelihood of occasional aspiration of sufficient pathogens to permit development of infection is high. Even if common respiratory diseases are not caused by aspiration of, or bacteraemia with, oral pathogens, their effects are likely to influence the development and progression of such diseases.
Cardiovascular Disease
It has been recognised that periodontal disease is a significant risk factor for development of cardiac disease, thromboembolism and stroke, which are still the leading causes of death in people. Anaerobic bacteria, such as Porphyromonas gingivalis, that enter the circulation activate thrombocytes resulting in their aggregation and obstruction of small blood vessels, which for example can result in insufficient flow through coronary arteries. Such bacteraemias may also cause degenerative changes on heart valves, coronary and other vessels, endocarditis, myocarditis or endocardiosis as well.9,10 Inflammatory periodontal disease is believed to be one of the factors in development of atherosclerosis.8 P. gingivalis has been isolated from atheromas of carotid and coronary artery, and has been cultivated in vitro or identified by PCR in the endothelium cells of endocardium and aorta.11 Patients with periodontal disease and atherosclerosis often have a common genetically determined phenotype of hyperinflammatory monocytes, which in contact with endotoxins (of periodontal and other gram- negative microflora) release increased amounts of IL-1, PGE2 and TNF-α: cytokines which accelerate development of atherogenesis and thrombosis.
Cardiovascular disease of various types is frequently identified in dogs, particularly those older than ten years of age, i.e., animals that are likely to have had periodontal disease for many years. Miniature and toy breeds are a risk group for development of both cardiovascular and periodontal disease and it is suspected that there may be genetic factors involved as there are in people. The most common pathology in a recent necropsy study of small poodles was chronic degeneration of the heart valves and swellings in the wall of coronary vessels in all cases. It cannot be excluded that in dogs with periodontal disease and endocardiosis there is concurrent impairment of microcirculation, leading to capillary rarefication and subsequent ischemia of the periodontium and myocardium, predisposing to periodontal disease and endocardiosis occurring in parallel, as seen in man.8 A further pathway that may link periodontal and cardiac disease is the influence of systemic inflammatory mediators on the myocardium. It has been shown that pro-inflammatory cytokines such as TNF α and IL-6 may cause anabolic changes in the myocytes through the activation of intracellular signaling, which leads to hypertrophy of the myocardium.8
Liver Disease
Extrahepatic bacterial infections that are associated with bacteraemia can cause intrahepatic cholestasis, and both parenchymal inflammation and portal fibrosis have been associated with periodontal disease in dogs.2 The level of histopathological changes in the poodle livers in the above mentioned study was statistically significant according to gender. In male dogs there was typically a moderate focal or diffuse inflammation and/or mild focal or multifocal fibrosis. In female dogs there were milder changes, primarily diffuse parenchymal or portal system inflammation. It is speculated that the difference in liver pathology between genders is connected with the greater total dental circumference, and consequently a larger average area of periodontal disease burden in the male population. Combined mild mononuclear infiltrates of portal tracts, foci of liver cells surrounded by neutrophils and macrophages, and mild hepatocellular vacuolar change were common findings. These changes, which are indicative of current or recent immune stimulation, can occur secondarily to a wide variety of extrahepatic disorders, such as chronic disease anywhere in the gastrointestinal tract including the oral cavity.12 As the oral cavity was the only site with gross evidence of inflammation in the studied animals, it is likely that the oral inflammation was a significant factor even if not the primary cause. It is considered likely that the significant correlation found between periodontal disease burden and liver pathology is an accurate indicator of the tendency for one or more of LPS from gram-negative periodonto-pathogenic bacteria, intact bacteria filtered from the circulation during bacteraemia, and inflammatory cytokines absorbed from periodontal lesions to activate the defensive cells of liver parenchyma resulting in the hepatic pathology.
Kidney Disease
Pyelonephritis and interstitial nephritis may also result from bacteraemia related to oral infection in dogs. Immune mediated kidney disease, particularly glomerulonephritis, is also considered to be a potential consequence of chronic low-grade bacteremia associated with periodontal disease.2 Glomerular localization of exogenous antigens occurs in bacteraemia associated with periodonto-pathogenic bacteria. These bacteria appear to have an affinity for endothelium and serum filtration in the kidneys will increase the likelihood of glomerular capillary walls being affected. Bacteria, free LPS and other antigens react with specific immunoglobulins to form immune complexes either locally within the kidney or in the circulation with deposition of complexes in the glomeruli associated with the process of serum filtration as urine is produced.13,14 Once formed, immune complexes activate complement and stimulate production of bioactive mediators such as cytokines, eicosanoids, growth factors and nitric oxide. They also stimulate mesangial cell proliferation and the production of the intracellular microfilament actin α SMA and extracellular matrix proteins. The glomerular and interstitial changes seen in necropsy studies of periodontal disease susceptible dogs are suggestive of immune complex-mediated damage, though this is yet to be confirmed. However, The strong correlation found between periodontal disease burden and extent of renal pathology suggest that periodontal disease contributes to the development of these lesions, most likely through chronic, persistent or repetitive insult to the kidney.
References
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