Inhibition of Cyclosporin A‐Induced Gingival Overgrowth by Azithromycin Through Phagocytosis: An In Vivo and In Vitro Study

Paik, Jeong Won; Kim, Chang Sung; Cho, Kyoo-Sung; Chai, Jung‐Kiu; Kim, Chong Kwan; Choi, Seong‐Ho

doi:10.1902/jop.2004.75.3.380

Cited by 30 publications

(26 citation statements)

References 36 publications

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“…In previous studies, collagen coated beads have been used to study the phagocytosis of individual beads [46][47][48]. In gingival cells, the presence of cyclosporin A was shown to inhibit collagen phagocytosis in vitro [48,49]. In the present study, the cells grown in the presence of cyclosporin A also displayed reduced production of new collagen.…”

Section: Discussionsupporting

confidence: 56%

Phagocytosis and remodeling of collagen matrices

Abraham

Dice

Lee

et al. 2007

Experimental Cell Research

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The biodegradation of collagen and the deposition of new collagen-based extracellular matrices are of central importance in tissue remodeling and function. Similarly, for collagen-based biomaterials used in tissue engineering, the degradation of collagen scaffolds with accompanying cellular infiltration and generation of new extracellular matrix is critical for integration of in vitro grown tissues in vivo. In earlier studies we observed significant impact of collagen structure on primary lung fibroblast behavior in vitro in terms of collagen uptake and matrix remodeling. Therefore, in the present work, the response of human fibroblasts (IMR-90) to the structural state of collagen was studied with respect to phagocytosis in the presence and absence of inhibitors. Protein content and transcript levels for Collagen I (Col-1), Matrix Metalloproteinase 1 (MMP-1), Matrix Metalloproteinase 2 (MMP-2), Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP-1), Tissue Inhibitor of Matrix Metalloproteinase 2 (TIMP-2), and Heat Shock Protein 70 (HSP-70) were characterized as a function of collagen matrix concentration, structure and cell culture time to assess effects on cellular collagen matrix remodeling processes. Phagocytosis of collagen was assessed quantitatively by uptake of collagen coated fluorescent beads incorporated into the pre-formed collagen matrices. Significantly higher levels of collagen phagocytosis were observed for the cells grown on the denatured collagen vs. native collagen matrices. Significant reduction in collagen phagocytosis was observed by blocking several phagocytosis pathways when the cells were grown on denatured collagen versus non-denatured collagen. Collagen phagocytosis inhibition effects were significantly greater for PDL57 IMR-90 cells versus PDL48 cells, reflecting a reduced number of collagen processing pathways available to the older cells. Transcript levels related to the deposition of new extracellular matrix proteins varied as a function of the structure of the collagen matrix presented to the cells. A four-fold increase in transcript level of Col-1 and a higher level of collagen matrix incorporation were observed for cells grown on denatured collagen versus cells grown on non-denatured collagen. The data suggest that biomaterial matrices incorporating denatured collagen may promote more active remodeling toward new extracellular matrices in comparison to cells grown on non-denatured collagen. A similar effect of cellular action toward denatured (wound-related) collagen in the remodeling of tissues in vivo may have significant impact on tissue regeneration as well as the progression of collagen-related diseases.

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Section: Discussionsupporting

confidence: 56%

Phagocytosis and remodeling of collagen matrices

Abraham

Dice

Lee

et al. 2007

Experimental Cell Research

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“…Previous studies of CsA-induced gingival overgrowth showed disturbances in collagen turnover (18,25). Although there is a potential role for increased collagen production in gingival overgrowth (26), we focused on the intracellular collagen degradation pathway by fibroblasts since this pathway is impaired in vivo (31,32,44). Collagen phagocytosis involves extension of fibroblast lamellipodia that engulf collagen fibrils (40), a process that requires extensive remodeling of the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin inhibition of collagen remodeling is mediated by gelsolin

Chan¹,

Arora²,

McCulloch³

2007

American Journal of Physiology-Cell Physiology

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Cyclosporin A (CsA) inhibits collagen remodeling by interfering with the collagen-binding step of phagocytosis. In rapidly remodeling connective tissues such as human periodontium this interference manifests as marked tissue overgrowth and loss of function. Previous data have shown that CsA inhibits integrin-induced release of Ca(2+) from internal stores, which is required for the binding step of collagen phagocytosis. Because gelsolin is a Ca(2+)-dependent actin-severing protein that mediates collagen phagocytosis, we determined whether gelsolin is a CsA target. Compared with vehicle controls, CsA treatment of wild-type mice increased collagen accumulation by 60% in periodontal tissues; equivalent increases were seen in vehicle-treated gelsolin-null mice. Collagen degradation by phagocytosis in cultured gelsolin wild-type fibroblasts was blocked by CsA, comparable to levels of vehicle-treated gelsolin-null fibroblasts. In wild-type cells treated with CsA, collagen binding was similar to that of gelsolin-null fibroblasts transfected with a gelsolin-severing mutant and treated with vehicle. CsA blocked collagen-induced Ca(2+) fluxes subjacent to bound collagen beads, gelsolin recruitment, and actin assembly at bead sites. CsA reduced gelsolin-dependent severing of actin in wild-type cells to levels similar to those in gelsolin-null fibroblasts. We conclude that CsA-induced accumulation of collagen in the extracellular matrix involves disruption of the actin-severing properties of gelsolin, thereby inhibiting the binding step of collagen phagocytosis.

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“…The dissolved drug was given by gastric syringe, each rat received 30 mg/kg daily. 15 Group III: The rats of this group were administered PNT after trituration with Tween 80 solution. They received PNT via subcutaneous injection twice daily for 6 weeks.…”

Section: Animal Subjectsmentioning

confidence: 99%