Wound Healing Modulators in a Tracheoplasty Canine Model

Abstract

Postsurgical tracheal stenosis results from fibrosis formation due to ischemia. There are healing modulators, hyaluronic acid (HA) and collagen polyvinylpyrrolidone (CPVP), which reduce collagen fibers formation. Thus we can hypothesize that the topical application of one of these modulators can diminish postsurgical tracheal scarring and stenosis. The aim of this work was to evaluate the macroscopic, microscopic, and biochemical changes of tracheal healing after the application of HA or CPVP in a canine tracheoplasty model. The study design was prospective experimental investigation in a canine model. Eighteen mongrel dogs underwent three cervical tracheal rings resection and end-to-end anastomosis. They were randomized into three groups according to treatment: group I (control group) (n = 6), topical application of saline solution on tracheal anastomosis; group II (n = 6), topical application of 15 microg HA on tracheal anastomosis; and group III (n = 6), topical application of 2.5 mg CPVP on tracheal anastomosis. They were evaluated clinical, radiological and tracheoscopically during 4 weeks. They were euthanized at the end of the study time. Macroscopic, microscopic, and biochemical changes of tracheal anastomosis healing were analyzed. Collagen formation was quantified by the Woessner method. All the animals survived the surgical procedure and study period. Macroscopic, radiologic, and endoscopic studies showed that animals in group I developed tracheal stenosis, inflammation, and firm fibrous tissue formation, and histological studies also showed severe inflammatory reaction and fibrosis formation. Groups II (HA) and III (CPVP) showed well-organized thin collagen fibers with minimal inflammatory response. Biochemical evaluation revealed a higher collagen concentration in group I animals (analysis of variance [ANOVA] p < .05 and Tukey p < .01). Thus, hyaluronic acid or collagen polyvinylpyrrolidone administered after tracheal anastomosis diminished the degree of stenosis and inflammatory reaction. Both modulators improved tracheal healing.

Effects of Pirfenidone and Collagen-Polyvinylpyrrolidone on Macroscopic and Microscopic Changes, TGF-β1 Expression, and Collagen Deposition in an Experimental Model of Tracheal Wound Healing

“…Conversely, the low levels of inflammation and fibrosis in the groups treated with Collagen-PVP and PFD may have been due to the anti-inflammatory and fibrinolytic effects of both drugs [1, 2, 11, 22], which prevent the accumulation of granulation tissue at the tracheal lesion site. These findings corroborate the results from other studies using Collagen-PVP and MMC as tracheal wound-healing modulators in dogs [10, 23] and the findings by Zhou et al, who observed that animals treated with PFD developed less tracheal fibrosis in a murine model of heterotopic tracheal transplantation [24]. …”

“…However, stridor disappeared during the second postsurgical week in animals from group II because of the anti-inflammatory effect of Collagen-PVP, which agrees with the findings of other studies that investigated the effect of this compound on tracheal wound healing [10]. Moreover, the effect of PFD, which was administered to group IV, on tracheal wound healing, has not yet been reported.…”

“…TSs are treated with endoscopic and surgical procedures combined with topical WHM application (e.g., MMC) to pharmacologically manipulate ECM formation and prevent tracheal restenosis. However, an optimal WHM that can prevent inflammation and does not require multiple endoscopic applications has not yet been identified [8–10]. Therefore, we herein assessed the effects of PFD on tracheal wound healing because this drug has shown antifibrotic, anti-inflammatory, and antioxidant properties in several tissues.…”

“…The animals in group I received 0.5 mL SS, whereas those in group II received 2.5 mg Collagen-PVP (Fibroquel, Aspid S.A de C.V., Mexico City; this dose is clinically used for skin and tendon problems and has been experimentally used in chronic TS) diluted in 0.5 mL distilled water [10]. Group III received 1.2 mg/kg MMC (Mixandex, Pisa, S.A. de C.V., Guadalajara, Mexico; this dose is used for the clinical treatment of TS) [9].…”

“…Specifically, mitomycin C (MMC) is the most commonly used WHM, but it has not demonstrated the desired success because it slows wound healing, predisposes patients to acute mucus accumulation, and causes defects in mucosal revascularization [8, 9]. Collagen-polyvinylpyrrolidone (Collagen-PVP) has also been used with good results but requires four weeks of intratracheal application [10], which complicates its use because patients must undergo general anesthesia. In this context, new WHMs that exhibit improved treatment efficacy are needed.…”