The Process of Acclimation to Chronic Hypoxia Leads to Submandibular Gland and Periodontal Alterations: An Insight on the Role of Inflammatory Mediators

Abstract

The exposition to hypoxia is a stressful stimulus, and the organism develops acclimation mechanisms to ensure homeostasis, but if this fails, it leads to the development of pathological processes. Considering the large number of people under hypoxic conditions, it is of utmost importance to study the mechanisms implicated in hypoxic acclimation in oral tissues and the possible alteration of some important inflammatory markers that regulate salivary and periodontal function. It is the aim of the present study to analyze submandibular (SMG) and periodontal status of animals chronically exposed to continuous (CCH) or intermittent (CIH) hypoxia in order to elucidate the underlying molecular mechanisms that may lead to hypoxic acclimation. Adult Wistar rats were exposed to CCH or CIH simulating 4200 meters of altitude during 90 days. Salivary secretion was decreased in animals exposed to hypoxia, being lower in CIH, together with increased prostaglandin E2 (PGE2) content, TBARS concentration, and the presence of apoptotic nuclei and irregular secretion granules in SMG. AQP-5 mRNA levels decreased in both hypoxic groups. Only the CCH group showed higher HIF-1α staining, while CIH alone exhibited interradicular bone loss and increased concentration of the bone resorption marker CTX-I. In summary, animals exposed to CIH show a worse salivary secretion rate, which related with higher levels of PGE2, suggesting a negative role of this inflammatory mediator during hypoxia acclimation. We link the weak immunorreactivity of HIF-1α in CIH with improper hypoxia acclimation, which is necessary to sustaining SMG physiology under this environmental condition. The alveolar bone loss observed in CIH rats could be due mainly to a direct effect of PGE2, as suggested by its higher content in gingival tissue, but also to the indirect effect of hyposalivation. This study may eventually contribute to finding therapeutics to treat the decreased salivary flow, improving in that way oral health.

Chronic Hypoxia‐Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL‐6/JAK2/STAT3/MMP‐9 Pathway

“…In order to understand how the IL-6/JAK2/STAT3/ MMP-9 pathway regulates the microvessels under hypoxia, the specific processes should be analyzed in detail. IL-6, one of the dominant inflammatory cytokines [24][25][26][27], markedly upregulates the phosphorylation of JAK2 by binding to IL-6 receptor α (IL-6Rα) and activating gp130 [12]. P-JAK2 subsequently induces STAT3 phosphorylation.…”

“…Other studies have validated this and have identified the pathways regulating the process [18][19][20][21][22][23]. Proinflammatory cytokine interleukin-6 (IL-6) released from inflammatory cells binds to IL-6 receptor α and active gp130 to induce the phosphorylation of JAK2 (P-JAK2), in response to hypoxia [24][25][26][27]. P-JAK2 promotes the overexpression of MMP-9 in the vascular endothelial cells, leading to angiogenesis and BM degradation by activating the phosphorylation of STAT3 tyrosine residues (P-STAT3) [7].…”

Altered production of reproductive neuropeptides in rats subjected to chronic intermittent hypoxia

“…Protocols were approved by the institutional Animal Care and Use Committee (IACUC, N o 11/06/2012-23) of the School of Dentistry, University of Buenos Aires. Rats were randomly assigned to one of three groups of ten animals each subject to the following conditions: Control group (C): normoxia; Chronic Intermittent Hypoxia (CIH): exposure to discontinuous hypoxia (600 mbar, equivalent to 4,000 meters of simulated altitude) in a simulated high altitude chamber for 18 h/d, five days a week for 30 days (time of exposure to hypoxia was approximately 50 % of the experimental period); Chronic Continuous Hypoxia (CCH): continuous exposure to the same ambient pressure in the simulated high altitude chamber as the CIH group but for 23.5 h/d seven days a week for 30 days (time of exposure to hypoxia was almost 100 % of the experimental period) [17]. Environmental oxygen pressure was 12.6 kPa during the hypoxic period in both hypoxic protocols.…”

High Altitude and Its Effects on Oral Health: A Review of Literature

“…Chronic exposure to hypoxia induced the expression of high levels of inflammatory mediators such as prostaglandin E2, decreased immunoreactivity of hypoxia-inducible factor 1α, and the presence of apoptotic nuclei and irregular secretion granules in oral tissue, indicating the damaging role of these inflammatory mediators during hypoxia. 36 Another study used a rat periodontitis model in a simulated high-altitude hypoxic environment to measure the association of cytokines and clinical periodontal parameters under hypoxic conditions and compare the findings with those obtained in normal conditions. The results showed an increase in tumor necrosis factor α and prostaglandin E2, and a decrease in interleukin-8 levels in the gingival crevicular fluid of the hypoxia group in relation to increased attachment loss, pocket depth, plaque index, and bleeding index.…”

“…Many studies have recorded the health problems related to living in or travelling to high altitudes, and have discussed the oral features of living at high altitudes, 13,14 including periodontal inflammation, 15,16 saliva production, 17 dental pain and anesthesia, 18 inflammatory mediators and bleeding index, 19 and dental fluorosis. 20 However, studies covering the effect of high altitudes on the oral cavity are relatively fewer, and many of them lack conclusive findings or require more detailed investigation.…”