Celecoxib, Angiogenesis, and Wound Healing

Introduction
Wounds and their healing are major issues in medicine, especially in surgery and dermatology and categorized into two major groups: acute and chronic. In the United State, (3-6) million individuals are suffering from chronic wounds [1]. Although chronic wounds can heal, a recurrence range of (23-70%) is reported, which depends on the etiology [2]. One of the most important complications associated with chronic wounds is infections that may lead to various outcomes [3]. In the wound healing process, different steps are involved, among which angiogenesis is very crucial. Suppression of this phenomenon could disturb the wound healing process [2].
Angiogenesis is the formation of new blood vessels from pre-existing ones under physiologic and or pathologic conditions such as tumor growth, psoriasis, rheumatoid arthritis, diabetic retinopathy, multiple evanescence white dot syndrome, corneal neovascularization, and other types of angiogenic-dependent pathological conditions [4-6]. In other words, only a few physiological processes like wound healing and the female reproductive cycle are dependent on angiogenesis [7, 8]. In wound healing, angiogenesis is very important due to its role in supplying nutrition and oxygenation for proliferating cells and also removing waste materials from both necrotic and proliferating tissues [9, 10]. Angiogenesis is induced by different cytokines such as Hypoxia-Inducible Factor α (HIF- α), Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), Matrix MetalloProteinases (MMPs), Platelet-Derived Growth Factor (PDGF), Angiopoietin 1 (Ang-1) and Tumor Necrosis Factor α (TNF- α). Under the cellular hyper-proliferation state, a hypoxic condition is induced, and cells begin to secret HIF-α which up-regulates VEGF gene expression as a key regulator of angiogenesis. VEGF is responsible for two main steps of vascularization: proliferation and migration of Endothelial Cells (ECs).
Also, MMPs, especially MMP-2, is responsible for the migration of proliferated ECs. TNF-α can stimulate the ECs strand formation in this system. Additionally, PDGF, which is widely secreted by ECs and activated macrophages, affect ECs strand formation. Another cytokine, bFGF, induces ECs chemotaxis, proliferation, and plasminogen activator expression. Ang-1, which seems to appear last in the angiogenesis process, affects ECs tube formation, inhibit their apoptosis and maturation of formed micro-vessels [4, 7, 11-14]. Also, it has been shown that cyclooxygenase-2 (COX-2) and its consequent products can induce angiogenesis via induction of VEGF, bFGF, and PDGF [15].
Hypothesis
Celecoxib could impair wound healing through inhibiting angiogenesis. In the following part, the mechanism of this action would be discussed.
Evaluation of hypothesis
As mentioned earlier, angiogenesis and inflammation are crucial steps during wound healing. Angiogenesis occurs in a milieu filled with various cytokines such as VEGF, MMP-2, bFGF, PDGF, HIF-α, TGF-ß, and PDGF [4, 7, 12-14]. In vivo study of retinal angiogenesis has shown that celecoxib can inhibit the induced angiogenesis via suppression of HIF-α and VEGF on a transcription level [16]. Also, it can suppress the expression of MMP-2 as Wang et al. mentioned in their study [17].
Additionally, celecoxib could inhibit angiogenesis induced by bFGF at in vivo models of corneal neovascularization in two separate studies [16, 18]. VEGF suppression has also been mentioned in many other studies which are mostly in vivo investigations [16-20]. Finally, it has been stated by El-Sayed et al. that celecoxib could decrease Ang-1 serum level in vivo. This COX-2 inhibitor can also inhibit inflammation besides angiogenesis through suppression of TNF-α as a shared cytokine in both mentioned steps [21].
Discussion
As stated before, wound healing is an important issue in medicine due to its complications. In this study, we hypothesized that celecoxib could impair the wound healing process through anti-angiogenic activity. As Fairweather et al. reported, celecoxib would inhibit wound healing in vivo model. Also, in the histological analysis, they showed that celecoxib could decrease the number of blood vessels significantly in comparison to the physiologic condition [22]. Besides, the other COX-2 inhibitor meloxicam was confirmed to inhibit wound healing as well as celecoxib at an in vivo model [23]. It has been reported that celecoxib does not affect wound healing in the mice model of hemophilia [24].
On the other hand, evidence has proved that hemophilic patients experience significant elevated angiogenic and inflammatory cytokines in their plasma in comparison to healthy individuals. According to a study by Hoffman et al., cutaneous wound healing is different in hemophilia B following the activation of angiogenesis pathway [25]. Thus any phenomena which change angiogenic or inflammatory cytokines as a pathological condition using anti-angiogenic or anti-inflammatory agents may only reduce the cytokine levels to the physiological baseline. This issue was also reported in a wound bearing squamous carcinoma cell VII [24].
Obviously, tumors would not grow bigger than a few cubic millimeters if they don’t reach new supply recourses, which in turn depend totally on tumor angiogenesis. Thus seeding a tumor beside the location of the wound could inhibit the suppressing effect of celecoxib by releasing the angiogenic factors from the tumor cells [5]. Both these two studies, claiming that celecoxib does not affect wound healing, were performed in pathological situations with the excessive secretion of angiogenic factors. According to the authors’ personal opinion, the inhibitory activity of celecoxib in wounds could be more important in wounds with tissue loss such as pilonidal cystectomy or anal fistulas compared to a surgical incision. Altogether, regarding the anti-angiogenic and anti-inflammatory potentials of celecoxib and the role of both processes in wound healing, authors hypothesized that celecoxib could negatively affect wound healing although further investigations (in non-pathological conditions) are still required to reach a decisive conclusion.
Ethical Considerations
Compliance with ethical guidelines
There was no ethical considerations to be considered in this research.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authors' contributions
All authors contributed in preparing this article.
Conflicts of interest
Authors declare no conflict of interest related to this study.
Acknowledgements
Authors are grateful for kind comments provided by Dr. Kamran Mansouri, Medical Biology Research Center (Kermanshah, Iran).