Cytokine-Mediated Inflammation in the Oral Cavity and Its Effect on Lipid Nanocarriers

Abstract

Topical drug administration to the oral mucosa proves to be a promising treatment alternative for inflammatory diseases. However, disease-related changes in the cell barrier must be considered when developing such delivery systems. This study aimed at investigating the changes in the lining mucosa caused by inflammation and evaluating the consequences on drug delivery systems such as nanostructured lipid carriers (NLC). For this, TR146 cells were treated with inflammatory cytokines and bacterial components. Cell viability and integrity, reactive oxygen species (ROS), and interleukin (IL)-8 release were used as endpoints to assess inflammation. Translocation of phosphatidylserine, cytoskeletal arrangement, opening of desmosomes, and cell proliferation were examined. Transport studies with NLC were performed considering active and passive pathways. The results showed that IL-1ß and tumor necrosis factor α induced inflammation by increasing IL-8 and ROS production (22-fold and 2-fold). Morphologically, loss of cell–cell connections and formation of stress fibers and hyperplasia were observed. The charge of the cell membrane shifted from neutral to negative, which increased the absorption of NLC due to the repulsive interactions between the hydrophobic negative particles and the cell membrane on the one hand, and interactions with lipophilic membrane proteins such as caveolin on the other.

Investigation of Cellular Interactions of Lipid-Structured Nanoparticles With Oral Mucosal Epithelial Cells

“…The uptake pathway, i.e., active versus passive and the respective routes were investigated using particle concentrations of 500 μg/ml and inhibitor concentrations that did not affect cell morphology. ( Tetyczka et al, 2021 ). Cells incubated at 4°C with 500 μg/ml particles showed no uptake regardless of the formulation tested, hence passive uptake could be excluded (data not shown).…”

“…Subsequently, TR 146 cells were pretreated with dynasore (i.e., 200 µM), chlorpromazine (i.e., 20 µM), genistein (i.e., 300 µM), and EIPA (i.e., 0.5 µM) for 40 min at 37°C respectively before incubation with the labeled SLN and NLC (i.e., 500 μg/ml) for 4 h at 37°C. ( Tetyczka et al, 2021 ). After 4 h, particles were removed and cells were washed with PBS.…”

“…Moreover, uptake into epithelial cells of the buccal mucosa occurred via active transport, which does not change even in the inflamed state and thus other physiological conditions present. ( Tetyczka et al, 2021 ).…”

Orofacial clefts lead to increased pro-inflammatory cytokine levels on neonatal oral mucosa

“…Considering systemic cytokine levels (in peripheral blood), infants with OFC (0-12 months) presented significantly increased levels of IL-17 and INF-γ compared to an age-matched control group, however, levels of IL-6 and IL-8 were similar in both groups ( 63 ), which is in contrast to our results found in tongue smear samples. TNF is a primary pro-inflammatory cytokine ( 37 ) and promotes vasodilatation, edema formation, leukocyte adhesion, regulation of blood coagulation ( 28 ). Remarkably, high levels of TNF were associated with surgical site infection ( 34 ) and worsening of the mucosal epithelial barrier function ( 40 , 41 ), while TNF inhibitor treatment was shown to reduce surgical site infection ( 35 , 36 ) ( Table 1 ).…”

“…Remarkably, high levels of TNF were associated with surgical site infection ( 34 ) and worsening of the mucosal epithelial barrier function ( 40 , 41 ), while TNF inhibitor treatment was shown to reduce surgical site infection ( 35 , 36 ) ( Table 1 ). IL1-β triggers primary pro-inflammatory reactions by the innate immune system, e.g., by activation of IL-8 ( 37 ), primary host defence responses to injury as well as enhancement of tissue damage in injury-associated mechanisms ( 44 ) ( Table 1 ). IL-6 promotes migration of immune cells to damaged sites ( 45 ) and increased levels were shown to alter tissue integrity ( 41 ) ( Table 1 ).…”