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

Abstract

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-1β, 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.

Association Between Salivary Cytokines, Chemokines and Growth Factors and Salivary Gland Function in Children with Chronic Kidney Disease

“…Although water-electrolyte imbalances undoubtedly play a role here, 27 it is speculated that inflammation may also contribute to hyposalivation and impaired protein secretion into saliva. The results of recent studies indicate the involvement of salivary cytokines, chemokines and growth factors in impairing the secretory function of the salivary glands in patients with chronic heart failure, 38 Hashimoto's disease, 39 psoriasis 40,41 or Sjogren's syndrome. 42,43 Since hyposalivation significantly reduces patients' quality of life, 44 determining its causes in children with CKD may be of great importance to both patients and physicians.…”

“…48 In patients with Sjogren's syndrome, salivary level of IL-6 has been shown to correlate positively with the size of lymphocytic infiltration in the labial salivary glands. 38,49,50 IL-6 enhances the local inflammatory process by inducing T-lymphocyte proliferation and B-lymphocyte differentiation, and reducing the number of Treg lymphocytes. 38,51,52 It has been observed that increased secretion of IL-1, TNF-α and INF-γ inhibits acetylcholine release in the salivary glands, causing impairment of the response of acinar cell, and is thus responsible for hyposalivation.…”

“…38,49,50 IL-6 enhances the local inflammatory process by inducing T-lymphocyte proliferation and B-lymphocyte differentiation, and reducing the number of Treg lymphocytes. 38,51,52 It has been observed that increased secretion of IL-1, TNF-α and INF-γ inhibits acetylcholine release in the salivary glands, causing impairment of the response of acinar cell, and is thus responsible for hyposalivation. 38,53 In addition, INF-γ decreases mucin production in the salivary acinar cells, 54 which may be an explanation of the changes in saliva viscosity in patients with CKD.…”

“…38,51,52 It has been observed that increased secretion of IL-1, TNF-α and INF-γ inhibits acetylcholine release in the salivary glands, causing impairment of the response of acinar cell, and is thus responsible for hyposalivation. 38,53 In addition, INF-γ decreases mucin production in the salivary acinar cells, 54 which may be an explanation of the changes in saliva viscosity in patients with CKD. 55 Although the evaluation of the salivary inflammatory profile does not indicate a particular dominance of any of the immune system branches, we observed a statistically significant increase in the concentration of all Th2 cytokines assayed (↑IL-4, ↑IL-5, ↑IL-6, ↑IL-9).…”

The NF-κB pathway plays a vital role in rat salivary gland atrophy model

“…Pathological conditions, such as obstructive factors, chronic heart failure, dementia, chronic kidney disease, psoriasis, and autoimmune diseases, such as Sjögren's syndrome and Hashimoto's disease, alter the function of salivary glands, which affects quality of life [ [5] , [6] , [7] , [8] ]. Obstructive sialadenitis and sialolithiasis induce chronic or acute inflammation and swelling of the salivary gland due to obstruction of the salivary duct [ 9 ].…”