Potential of tadalafil and tadalafil-cellulose nanocomposite in preventing postsurgical abdominal adhesions in a rat cecal abrasion model

Abstract

The formation of postoperative intra-abdominal adhesions is a significant challenge in veterinary practice worldwide. Thus, several attempts have been made to identify agents that prevent the occurrence of these postsurgical adhesions. However, finding an ideal and effective agent remains a challenge. Herein, we investigate the potential of tadalafil and tadalafil/cellulose composite as promising therapeutics for preventing postsurgical intra-abdominal adhesions. A cecal abrasion model was established in 30 rats, which either left untreated or treated with tadalafil, cellulose, or tadalafil/cellulose. After 2 weeks, the adhesion formation was evaluated based on gross appearance, oxidative stress markers, pro-inflammatory cytokines, histopathological analysis, and immunohistochemical staining. Compared to the adhesion group, gross and histopathological findings revealed that both the tadalafil and cellulose groups significantly decreased adhesion formation, with better results observed after tadalafil treatment. Importantly the tadalafil/cellulose treatment completely prevented adhesion formation. Additionally, the treated groups showed reduced levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), while increasing the level of reduced glutathione (GSH) compared to the adhesion group. Furthermore, the treated groups reduced the expression of macrophage markers. These findings suggest that the intra-abdominal application of tadalafil and tadalafil/cellulose following abdominal surgery holds promise as a clinical strategy to prevent postsurgical intra-abdominal adhesions, with tadalafil/cellulose demonstrating superior efficacy.

Keywords: Adhesions; Anti-adhesion; Cellulose; Intra-abdominal; Postsurgical; Tadalafil.

Fig. 1

Graphical summary illustrating the overall study design, including material synthesis and characterization, in vitro cytotoxicity testing, and in vivo evaluation in a rat model of intra-abdominal adhesions (Created in BioRender, https://BioRender.com/7lp96sr).

Fig. 2

Characterization of tadalafil/cellulose. (A) Preparation procedure and (B) XRD characterization of tadalafil/cellulose.

Fig. 3

Cytotoxicity assay in vitro. Cell viability of mouse embryonic fibroblast cells determined by the MTT assay. Cells were treated with tadalafil, cellulose, or a combination of tadalafil and cellulose for 48 h. Each bar represents the mean ± SD of cell viability percentage from three independent experiments (n = 8). The groups that labeled with different letters were statistically significant (p < 0.05), while groups having the same letter were insignificant. Differences were evaluated using one-way ANOVA followed by Tukey’s HSD post hoc test.

Fig. 4

Surgical establishment of cecal abrasion model. (A) Strict aseptic preparation, (B) celiotomy, (C) cecal exteriorization (yellow asterisk), (D) induction of cecal abrasion (yellow asterisk), (E) local application of tadalafil powder on the abraded cecum, (F) application of a cellulose sheet (red arrow), (G) application of a tadalafil/cellulose sheet (dark blue arrow), and (H) abdominal wall suturing.

Fig. 5

Gross appearance findings of intra-abdominal adhesion formation. The adhesion group showed severe intra-abdominal adhesions (A, B). The sham group displayed no abdominal adhesions (C). The gross appearance in tadalafil-treated group revealed no abdominal adhesions formation (D). The cellulose-treated group showed moderate abdominal adhesions (E). No adhesions were observed in the tadalafil/cellulose-treated group (F). W = abdominal wall, yellow asterisk: cecum, red arrow: adhesion bands.

Fig. 6

Biochemical indicators of the adhesion formation. (A) MDA (µmol/L), (B) GSH (µg/mL), (C) TNF-α (pg/mL), and (D) IL-6(pg/mL). The groups that labeled with different letters were statistically significant (p < 0.05), while groups having the same letter were insignificant. Differences were evaluated using one-way ANOVA followed by Tukey’s HSD post hoc test.

Fig. 7

Histopathological examination of intestine and adhesion tissue by H&E staining. The adhesion group displayed (A, B) an adhesion site between intestines (star), and (C, D, E) infiltration of neutrophils (star), infiltration between mucosal intestinal glands with mononuclear inflammatory cells and giant cells (arrows). The tadalafil-treated group showed (F, G, H) no adhesion, and (I, J) hyperemia of blood vessels (notched arrow) with mild mucosal inflammatory cell infiltration (arrow). The cellulose-treated group showed (K, L) an adhesion site between intestines (star), and (M, N, O) giant cells (arrows), mucosal inflammatory cellular infiltration (star). The tadalafil/cellulose-treated group displayed (P, Q) no adhesion, while (R) showed giant cells (notched arrow). The sham group (S) showed no adhesion and (T) normal intestinal mucosa. The scale bars in panels (A, B, G, K, L, P, and Q) = 200 μm, panels (F, H, M, and S) = 100 μm, (C, D, E, I, J, N, O, R, and T) = 20 μm.

Fig. 8

Immunohistochemical staining for macrophage marker (Anti-CD163 antibody) in the intestine and adhesion site. (A, B) The adhesion group showed severe positive reaction with a severe density for macrophages. (C) The tadalafil-treated group, (D) The cellulose-treated group, and (E) the tadalafil/cellulose-treated group displayed no adhesion but showed a moderate positive reaction with moderate macrophage density (brownish cytoplasmic stain). (F) The sham group revealed no reaction. The scale bars in panels (A, D, and E) = 200 μm, panels (B, C, and F) = 100 μm.