Could inflammation contribute to salivary gland dysfunction in patients with chronic heart failure?

Heart failure (HF) is one of the leading causes of death worldwide. HF results not only in cardiovascular dysfunction, but also numerous pathologies in the oral cavity and salivary glands. The present study is the first to evaluate whether salivary inflammatory and anti-inflammatory factors may be related with the occurrence of hyposalivation in HF patients. We also evaluated the potential of salivary biomarkers in the diagnostics of HF. The study included 30 women with HF and 30 sex- and age-matched healthy controls. We demonstrated significantly higher levels of pro-inflammatory cytokines, anti-inflammatory cytokines, Th1, Th2, Th17, chemokines and growth factors in unstimulated saliva of HF patients compared to controls. However, the results do not indicate dominance of either branch of the immune response. The concentration of selected biomarkers is significantly higher in patients with HF and salivary gland dysfunction compared to patients with normal saliva secretion and healthy subjects (IL-1ß, TNF-α, IL-7, IL-13, INF-γ, IL-12, IL-15, IL-5, IL-6, IL-9, IL-17, MCP-1/CCL-2, EOTAXIN/CCL11, RANTES/CCL5, GM-CSF, VEGF, FGF basic, PDFG-BB). Multivariate regression analysis showed that the content of salivary cytokines, chemokines and growth factors is highly dependent on salivary gland function, i.e. salivary flow rate, total protein content and amylase activity. Using receiver operating characteristic (ROC) analysis, we showed that salivary TNF-α, INF-γ, IL-12 and EOTAXIN/CCL11 differentiated patients with HF and hyposalivation with the highest sensitivity and specificity compared to patients with normal salivary secretion and controls. Interestingly, the content of some pro- and anti-inflammatory mediators in saliva significantly exceeds their concentration in plasma. In addition, salivary biomarker levels do not reflect their plasma content, which may suggest a different nature/severity of inflammatory changes at the central (blood) and local (salivary) levels. Although our study was purely observational, the significantly higher concentration of inflammatory parameters in saliva compared to plasma, as well as the lack of saliva-blood correlation, may suggest increased production/secretion of these compounds in salivary cells of HF patients. ROC analysis did not confirm the diagnostic utility of salivary cytokines and chemokines in the differential diagnosis of HF patients.

Enhanced Inflammation and Nitrosative Stress in the Saliva and Plasma of Patients with Plaque Psoriasis.

Psoriasis is the most common inflammatory skin disease, characterized by the release ofproinflammatory cytokines from lymphocytes, keratinocytes, and dendritic cells. Although psoriasis is considered an immune-mediated inflammatory disease, its effect on secretory activity of salivary glands and quantitative composition of saliva is still unknown. The aim of this study was to evaluate the secretion of saliva as well as several selected inflammation and nitrosative stress biomarkers in unstimulated and stimulated saliva as well as plasma of psoriasis patients. We demonstrated that, with progressing severity and duration of the disease, the  secretory function of the parotid and submandibular salivary glands is lost, which is  manifested as decreased unstimulated and stimulated saliva secretion and reduced salivary amylase activity and total protein concentration. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and interferon-gamma (INF-α) were significantly higher, whereas interleukin-10 (IL-10) content was considerably lower in unstimulated and stimulated saliva of patients with psoriasis compared to the controls, and the changes increased with the disease duration. Similarly, we observed that the intensity of nitrosative stress in the salivary glands of psoriasis patients depended on the duration of the disease. By means of receiver operating characteristic (ROC) analysis, we showed that the evaluation of nitric oxide (NO), nitrotyrosine, and IL-2 concentration in non-stimulated saliva with high sensitivity and specificity differentiatedpsoriasis patients on the basis of the rate of saliva secretion (normal salivation vs. hyposalivation). In summary, the dysfunction of salivary glands in psoriasis patients is caused by inflammation and nitrosative stress.

Salivary Antioxidants and Oxidative Stress in Psoriatic Patients: Can Salivary Total Oxidant Status and Oxidative Status Index Be a Plaque Psoriasis Biomarker?

The aim of our research was to evaluate redox balance parameters and biomarkers of oxidative stress (OS) in nonstimulated and stimulated saliva as well as the blood of patients with plaque psoriasis compared to healthy controls. The study involved 40 patients with plaque psoriasis and 40 generally healthy subjects matched by age and gender to the study group patients. We assayed the concentration/activity of antioxidant enzymes: salivary peroxidase (Px), catalase (CAT), and superoxide dismutase (SOD) measured in unstimulated saliva (NWS), stimulated saliva (SWS), and erythrocytes. In plasma as well as NWS and SWS, we measured the concentration/activity of reduced glutathione (GSH), total antioxidant potential (TAC), total oxidative status (TOS), oxidative stress index (OSI), and markers of oxidative modification of proteins: advanced glycation end products (AGE), advanced oxidation protein products (AOPP), and lipid oxidation products: malondialdehyde (MDA) and total lipid hydroperoxide (LOOH). In NWS and SWS, we also evaluated the rate of reactive oxygen species (ROS) production. The concentration of Px, CAT, and SOD was significantly higher in NWS of patients with plaque psoriasis vs. healthy subjects. In SWS of psoriatic patients, we observed considerably higher concentration of Px and CAT, and in erythrocytes of patients with plaque psoriasis, the concentration of GPx and CAT was significantly higher compared to that in the controls. The levels of AOPP, AGE, MDA, and LOOH were considerably higher in NWS, SWS, and plasma of the study group compared to the controls. The concentration of total protein and salivary amylase was significantly lower in NWS and SWS of psoriatic patients compared to the healthy control. In the course of plaque psoriasis, we observed redox imbalances with prevalence of oxidation reactions. Mechanisms involved in the synthesis/secretion of proteins and activity of amylase were depressed in both glands of psoriatic patients; however, they were more inhibited in the parotid gland compared to the submandibular gland. TOS concentration and OSI value in NWS and SWS may serve as diagnostic biomarkers of plaque psoriasis.

Antioxidant Defense, Oxidative Modification, and Salivary Gland Function in an Early Phase of Cerulein Pancreatitis.

Acute pancreatitis (AP) is a multifactorial disease characterized by necroinflammatory changes of the pancreas. Our study is the first study which evaluated the relationship between the free radical production, enzymatic and nonenzymatic antioxidants, oxidative damage, and secretory function of the salivary glands of AP rats. Male Wistar rats were divided equally into 2 groups: control (n = 9) and AP (n = 9). AP was induced by intraperitoneal injection with cerulein and confirmed by higher serum amylase and lipase. We have demonstrated that the superoxide dismutase and glutathione reductase activities, as well as reduced glutathione concentration, were significantly decreased in both the parotid and submandibular glands of AP rats as compared to the control rats. The production of free radicals evidenced as dichlorodihydrofluorescein assay and the activity of NADPH oxidase and xanthine oxidase and IL-1ß concentration were significantly higher in the parotid and submandibular glands of AP rats compared to the controls. In AP rats, we also showed a statistical increase in oxidation modification products (advanced glycation end products and advanced oxidation protein products), salivary amylase activity, and significant decrease in the total protein content. However, we did not show apoptosis and any morphological changes in the histological examination of the salivary glands of AP rats. To sum up, cerulein-induced AP intensifies production of oxygen free radicals, impairs the redox balance of the salivary glands, and is responsible for higher oxidative damage to these glands. Interestingly, oxidative modification of proteins and dysfunction of the antioxidant barrier are more pronounced in the submandibular glands of AP rats.