The Potential Use of Cannabis in Tissue Fibrosis

Abstract

Fibrosis is a condition characterized by thickening or/and scarring of various tissues. Fibrosis may develop in almost all tissues and organs, and it may be one of the leading causes of morbidity and mortality. It provokes excessive scarring that excels the usual wound healing response to trauma in numerous organs. Currently, very little can be done to prevent tissue fibrosis, and it is almost impossible to reverse it. Anti-inflammatory and immunosuppressive drugs are among the few treatments that may be efficient in preventing fibrosis. Numerous publications suggest that cannabinoids and extracts of Cannabis sativa have potent anti-inflammatory and anti-fibrogenic properties. In this review, we describe the types and mechanisms of fibrosis in various tissues and discuss various strategies for prevention and dealing with tissue fibrosis. We further introduce cannabinoids and their potential for the prevention and treatment of fibrosis, and therefore for extending healthy lifespan.

Keywords: Cannabis sativa; anti-fibrotic; cannabinoids; fibrosis; inflammation.

FIGURE 1

Phases of wound healing. Phase 1, hemostasis is the process of clot formation to stop bleeding, and includes steps such as vasoconstriction, aggregation of platelets and migration of leukocytes. Phase 2, inflammation is the process of cleaning the wound and preparing for the formation of new blood vessels. It includes processes such as release of antibacterial molecules by neutrophils, engulfing of pathogens and debris by macrophages, and release of angiogenic substances to stimulation angiogenesis and granulation. Phase 3, proliferation (or granulation) – the process allowing to bring the wound edges together and seal it. It includes proliferation of the wound by fibroblasts, with secretion of glycoproteins and collagen, followed by migration of epithelial cells from the wound edges and formulation of granulation tissues. Phase 4, remodeling (or maturation) phase is mostly a continuation of proliferation phase resulting in formation of proper tissue.

FIGURE 2

A clot formation cascade. There are three steps of the clotting (coagulation) cascade: the intrinsic pathway (factors XII, XI, IX, and VIII), the extrinsic pathway (factor VII), and the common pathway. During clotting, cascade factor X may be activated by the extrinsic and intrinsic pathways. The common pathway consist of steps from the activation of factor X to the clot formation. Factors that are activated are shown with a lowercase “a”.

FIGURE 3

Phases of proliferation and granulation.

FIGURE 4

Myofibroblast origin in fibrosis. Resident fibroblasts, pericytes, circulating progenitor cells (CD34⁺, CD45⁺, bone marrow–derived mesenchymal stem cells (MSC) transition, mesothelial cells undergoing mesothelial-to-mesenchymal transition (MMT), epithelial cells undergoing epithelial to mesenchymal transition (EMT) and endothelial cells undergoing endothelial-mesenchymal transdifferentiation (EndMT) are all known sources of myofibroblasts in various fibrotic diseases. ECM, extracellular matrix; TGF-β, transforming growth factor-β.

FIGURE 5

Effect of cannabinoids on various stages of wound healing in view of preventing/treating fibrosis. During the first stage of wound healing cannabinoids are responsible for inhibiting immune response by suppressing the release of immune cells into the injury cite and by inhibiting Th1 response and main pro-inflammatory cytokines (IL-2, IL-6, IL-1β, IFN-γ, TNF-α, TGF-β, NF-kB) (Watzl et al., 1991; Srivastava et al., 1998; Dinu et al., 2020). During exudation stage, cannabinoids inhibit the angiogenesis (Wietecha and DiPietro, 2013). Cannabinoids also actively contribute to the proliferation stage by suppressing chronic inflammation (Costa et al., 2007; Gallily et al., 2018), myofibroblast activation (Garcia-Gonzalez et al., 2009), the excessive deposition of ECM components (Garcia-Gonzalez et al., 2009) and normalization of TIMP-MMP imbalance (Garcia-Gonzalez et al., 2009).