Fcell 09 715380

REVIEW
published: 11 October 2021

doi: 10.3389/fcell.2021.715380
The Potential Use of Cannabis in

Tissue Fibrosis
Nazar Pryimak, Mariia Zaiachuk, Olga Kovalchuk* and Igor Kovalchuk*
Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
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
Edited by: discuss various strategies for prevention and dealing with tissue fibrosis. We further
Susanne Sattler, introduce cannabinoids and their potential for the prevention and treatment of fibrosis,
Imperial College London,
United Kingdom
and therefore for extending healthy lifespan.
Reviewed by: Keywords: fibrosis, anti-fibrotic, Cannabis sativa, cannabinoids, inflammation
Selvi Enrico,
Siena University Hospital, Italy
Elaine Cristina Dalazen Gonçalves, INTRODUCTION
Federal University of Santa Catarina,
Brazil
Fibrosis is a pathology associated with the replacement of parenchyma with connective tissue
*Correspondence: during the healing process. Fibrosis is defined as an excessive growth, stiffness, and sometimes
Olga Kovalchuk scarring of different tissues or organs along with an imputed overaccumulation of extracellular
[email protected]
matrix (ECM) components and collagen (Liu, 2011). Fibrotic illness is not well understood, it has
Igor Kovalchuk
[email protected]
a poor outcome and is mainly untreatable, all of which is compared to the terminal stage of cancer
(Wernig et al., 2017). This condition is a lifelong pathological anomaly that may occur in various
Specialty section: organs (Table 1), with a higher frequency in the skin, liver, heart, kidneys, and lungs.
This article was submitted to Different types of fibrosis have been recognized based on anatomical location such as
Molecular and Cellular Pathology, pulmonary [idiopathic pulmonary fibrosis (IPF), cystic fibrosis, emphysema], liver (cirrhosis,
a section of the journal portal hypertension, hepatocellular carcinoma) or skin (keloids, systemic sclerosis). The most well-
Frontiers in Cell and Developmental known and studied example of fibrosis is IPF. This condition is a lifelong, incurable illness targeting
Biology
lungs. This disease usually affects middle-aged people and older adults and is characterized by a
Received: 26 May 2021 long-lasting cough along with difficulties in breathing of an unknown origin; besides IPF is very
Accepted: 06 September 2021
difficult to diagnose. Many IPF patients struggle with an acute worsening of breathing that is
Published: 11 October 2021
correlated with high mortality. The progression rate of this condition is very unpredictable. Some
Citation: patients can deteriorate very quickly, while others may remain asymptomatic for many years. There
Pryimak N, Zaiachuk M,
is no generally approved treatment for this disease. The development of treatments is focused on
Kovalchuk O and Kovalchuk I (2021)
The Potential Use of Cannabis
fibroproliferation and fibrogenesis (Liu, 2011; Fujimoto et al., 2015; Hoyer et al., 2019). Because of
in Tissue Fibrosis. insensitivity to pharmacological treatments, an average survival time is 3 years.
Front. Cell Dev. Biol. 9:715380. Epidemiological data on fibrosis in different organs is well documented in the literature. For
doi: 10.3389/fcell.2021.715380 example, an incidence of IPF varies between 0.6 and 17.4 per 100,000 population per year
Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 October 2021 | Volume 9 | Article 715380
Pryimak et al. Cannabinoids and Tissue Fibrosis
TABLE 1 | Main types of fibrosis.
Organ/tissue Type of fibrosis References
Skin Hypertrophic scar Rabello et al. (2014)

Systemic sclerosis Allanore et al. (2015)
Heart Cardiac fibrosis Hinderer and Schenke-Layland (2019)
Hypertrophic cardiomyopathy Ho et al. (2010)
Cardiac dysfunction Khan and Sheppard (2006)
Valvular disease
Arrhythmia
Bone marrow Myelofibrosis Zahr et al. (2016)
Myelodysplastic syndrome Hinderer and Schenke-Layland (2019)
Chronic myelogenous leukemia
Liver Cirrhosis Šmíd (2020)
Portal hypertension
Hepatocellular carcinoma
Retroperitoneum Retroperitoneal fibrosis Vaglio and Maritati (2016)
Gut Intestinal fibrosis Hinderer and Schenke-Layland (2019)
Enteropathies
Inflammatory bowel disease
Joint Arthrofibrosis Usher et al. (2019)
Brain and nervous system Glial scar Hinderer and Schenke-Layland (2019)
Alzheimer
Eye Subretinal fibrosis Friedlander (2007)
Epiretinal fibrosis Khaw et al. (2020)
Vision loss
Lung Idiopathic pulmonary fibrosis Barratt et al. (2018)
Cystic fibrosis Friedlander (2007)
Pulmonary hypertension Smith et al. (2013)
Thromboembolic disease Farghaly and El-Abdin (2015)
Mediastinum Mediastinal fibrosis Rajput et al. (2000)
Pancreas Pancreatic fibrosis Klöppel et al. (2004)
Cystic fibrosis Madácsy et al. (2018)
Chronic pancreatitis Klöppel (2007)
Duct obstruction Apte et al. (2011)
Kidney Renal fibrosis Liu (2011)
Cystic fibrosis Yahiaoui et al. (2009)
Nephrogenic systemic fibrosis Waikhom and Taraphder (2011)
Chronic kidney disease Panizo et al. (2021)
Renal anemia Xiao and Liu (2013)
(Ley and Collard, 2013), two third of all patients were 60 years may be serve as useful additives to treatment of fibrosis. In
and above, and the highest prevalence was reported among this review, we will cover the pathology of fibrosis and current
patients of 80 years and above – 165.9 per 100,000 population therapy of fibrosis as well as introduce basic components of
(Raimundo et al., 2016). In Caucasians, cystic fibrosis occurs endocannabinoid system (ECS) and propose potential use of
roughly in 1 in 3,000–4,000 births; and among other races, cystic cannabinoids for treatment of fibrosis.
fibrosis is less frequent, 1 in 4,000–10,000 in Latin Americans
and 1 in 15,000–20,000 in African Americans, and even less in
Asian Americans (Sanders and Fink, 2016). As to liver cirrhosis, PHASES OF NORMAL WOUND HEALING
according to 2017 data, 112 million compensated cases were AND FIBROSIS
reported worldwide (Sepanlou, 2020), and in patient who were
more than 65 years old, a risk of severe liver fibrosis was 3.78 In most cases, fibrosis occurs after acute or more often chronic
times higher (Kim et al., 2015). Also, more than 100 million cases damage to tissues, followed by abnormal repair. There are
of keloid are reported annually worldwide (Gauglitz et al., 2011; two ways of repair of the injured tissues. The first one is
Li et al., 2017). the regeneration by the propagation of undamaged cells of
There is generally no good treatment of fibrosis and complete parenchyma and the maturation of stem cells – normal wound
recovery is nearly impossible. Treatment includes various anti- healing process. The second one is scar tissue formation through
inflammatory and anti-fibrotic agents with various degree of the accumulation of connective tissues – tissue fibrosis. The
success. In this respect, cannabinoids and Cannabis sativa regeneration is a possibility of damaged tissues to be repaired
extracts, known for their strong anti-inflammatory potential, and their defective elements to be restored. Cells that remain
undamaged are able to proliferate and maintain the structure fibrogenesis are summarized below (Table 2; Newton and Dixit,
of the tissue. In some cases, fibrosis may occur due to a critical 2012; Kendall and Feghali-Bostwick, 2014).
tissue injury or as a result of the inability of injured tissue
to accomplish the repair. Fibrosis occurs due to either a large The Third Phase – Proliferation and Granulation
amount of collagen deposition associated with the long-lasting Cell proliferation is an essential component of tissue repair,
inflammation or ischemic necrosis. Cell proliferation is handled wound healing and fibrogenesis. There are several types of cells,
by growth factors, although the central role is played by ECM and such as epithelial cells, endothelial cells, and fibroblasts
maturation of stem cells (Occleston et al., 2010). that participate in fibrogenesis and normal process of
Different types of cells, such as fibroblasts, vascular endothelial healing of the wound.
cells, and some fragments of injured tissues proliferate along with Mesothelial cells originate from the embryonic mesoderm and
the repair of damaged tissues. In fibrosis and scarring, tissue play an essential role during trauma or infection. For instance,
repair is characterized by the proliferation of connective tissues in pleural injuries, they assist in transporting white cells. Also, as
rather than parenchymal tissues that happens upon normal a result of mesothelial-to-mesenchymal transition (MMT), these
regeneration (Galliot et al., 2017). cells, might be genetically reprogrammed after the influence of
specific stimuli. In a recent mouse model, the lineage analysis of
Phases of Wound Healing stem cells demonstrated that MMT increased the proliferation of
Wound healing consists of four main phases, including myofibroblasts and hepatic satellite cells during liver fibrogenesis
hemostasis, inflammation, proliferation or granulation and (Tirado and Koss, 2018).
remodeling or maturation, each phase lasting from days to Fibrocytes are of a mesenchymal origin and are phenotypically
months (Figure 1). inactive due to a low amount of rough endoplasmic reticulum.
Abnormal wound healing resulting in scar formation These cells produce fibroblastic components such as collagen,
also includes similar phases/steps, such as inflammation, fibronectin, and vimentin. When influenced by TGF-β, they
cell proliferation, and remodeling, but is characterized by can produce alpha-smooth muscle actin (α-SMA) which
more extensive deposition of collagen, fibrin, fibronectin, etc. plays a role in angiogenesis and immunity. Fibrocytes
(Profyris et al., 2012). can also migrate to the damaged area with blood flow
(de Oliveira and Wilson, 2020).
The First Phase – Hemostasis Fibroblasts originate from the embryonic mesoderm tissues.
The most crucial step is not to restore a tissue but to stop Due to the chemotaxis feature, fibroblasts are able to migrate
bleeding from the injured place. Coagulation starts exactly after within tissue in response to chemical stimuli. In case of injury,
trauma and finishes within hours. Collagen assists this process they can cause contraction of the matrix that leads to the
in the damaged area. Hemostasis consists of two subphases, sealing of the open wound. Fibroblasts play an important role in
primary and secondary hemostasis. Primary hemostasis is the fibrogenesis, for example, TGF-β1 dependent differentiation into
formation of a plug at the injured place where endothelial myofibroblasts (Weiskirchen et al., 2019).
cells become exposed. In the secondary hemostasis, there are Epithelial cells are located in different areas of the body,
two main pathways of blood clotting: the extrinsic and the such as skin, urinary tract, blood vessels, and internal organs.
intrinsic pathways, and they come together in the common One of the critical features is their ability to differentiate
pathway. The extrinsic pathway is a primary stage in plasma into different types of cells. During epithelial-to-mesenchymal
mediated secondary hemostasis. Due to tissue damage, tissue transition (EMT), epithelial cells become transited cells that
factor (TF also known as platelet tissue factor or factor III) become sensitive to the fibroblast’s specific protein (FSP1). The
is released in the plasma, which results in binding of factor plasticity of epithelial cells allows them to become a source of
VIIa and calcium to boost the activation of factor X to Xa myofibroblasts in the damaged cells (Macara et al., 2014).
(Figure 2). The intrinsic pathway includes factors I (fibrinogen), Endothelial cells are mainly responsible for the formation of a
II (prothrombin), IX (Christmas factor), X (Stuart–Prower barrier in the endothelium of capillaries, venules, vein, arterioles,
factor), XI (Plasma thromboplastin), and XII (Hageman factor) and arteries. Being stimulated by TGF-β, endothelial cells can
(Robertson and Miller, 2018). The common pathway includes release α-SMA and become able to convert into mesenchymal
steps from the activation of factor X to the formation of active cells (endothelial-to-mesenchymal-transition, EndMT). It was
thrombin which brakes fibrin into a cross-linked complex. demonstrated that EndMT could lead to fibrosis in the organs
such as heart, kidney, and lungs (Sakai and Tager, 2013).
The Second Phase – Inflammation Pericytes are fibroblast-like cells that surround endothelial
Inflammation plays a central role in normal wound healing and cells in blood vessels. Pericytes are able to contract and
fibrosis. Tissue repair and regeneration also depend on the extent consequently control blood flow. In the case study, it was
of injury and inflammation. When the injury is extensive in the suggested that this type of cells produce α–SMA, neural/glial
presence of chronic inflammation, repair may predominate even antigen (NG2) and platelet-derived growth factor receptor-
when the damaged cells can regenerate. β (PDGFR-β). Moreover, they are a source of myofibroblasts
In normal circumstances, the inflammatory in pulmonary tissues. Another study reported that Foxd1
microenvironment quickly handles the damaged particles progenitor-derived pericytes prominently lead to the lung fibrosis
or pathogens. The essential factors of inflammation and (Sakai and Tager, 2013).
Hemostasis 1-3 days
Inflammaon 2 weeks
Proliferaon 5 weeks
Remodeling Up to 2 years
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.
Intrinsic pathway Extrinsic pathway
Contact activation Injury
Tissue
XII XIIa factor (TF) VIIa VII
XI XIa
IX IXa TF-VIIa
VIII, Platelets, Ca2+
Xa X
X Xa Common pathway
Prothrombinase complex, VIII, Platelets, Ca2+

Prothrom Thromb XIII
bine (II) ine (IIa)
XIIIa
Fibrino Fibrin
gen (I) (Ia)
Clot formaon
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”.
Vascular smooth muscle cells are responsible for the relaxation There are two main processes involved in proliferation phase
and contraction of blood vessels. As a result of the injury, they of repair: formation of granulation tissues and wound contraction.
produce α–SMA, vimentin, desmin, and other compounds. It has Wound contraction usually starts on day 2–3 and is finished
also been shown that collagen type I is induced by bradykinin within 2 weeks. The primary cells that are responsible for this
secretion in vascular smooth muscle cells through the TGF-β1 process are myofibroblasts, the unique cells that have features of
activation (Liu et al., 2017). fibroblasts and smooth muscle. The main role of these cells is
TABLE 2 | Key mediators of inflammation and fibrogenesis.
Substance Production site Effects References
Profibrotic TGFβ White blood cells Transformation of resident (subcutaneous, pulmonary, etc.) Frangogiannis (2020)
factors acting fibroblasts to myofibroblasts.
on fibroblasts Stimulation of collagen and fibronectin transcription.
Stimulation of resting monocytes and inhibition of activated
macrophages.
IL-1β Fibroblasts, macrophages Inflammation promotion and fibrotic responses (in part, through Lopez-Castejon and
activation of TNFα). Brough (2011)
IL-6 T cells, skeletal muscle cells, Regulation of inflammation (pro- and anti-inflammatory). Tanaka et al. (2014)
macrophages Stimulation of cellular differentiation and fibrosis.
IL-13 Mast cells, T lymphocytes, Stimulation of TGFβ production, proliferation of fibroblasts, Marone et al. (2019)
eosinophils and basophils collagen and MMP production.
IL-33 Smooth muscle cells, epithelial Signals through ST2 to initiate and enhances profibrogenic Li et al. (2014)
and endothelial cells cytokine production in a macrophage-dependent manner.
TNFα Macrophages, T lymphocytes, Stimulation of inflammation and fibrosis, in part through TGF-β Yoshimatsu et al. (2020)
NK cells, mast cells, eosinophils signaling pathway, activation of myofibroblasts and increased
secretion of MMPs.
FGFs Various parenchymal cells Fibrosis enhancement through binding and activation of Xie et al. (2020)
fibroblast growth factor receptor (FGFR).
PDGF Platelets, smooth muscle cells, Stimulation differentiation, proliferation, and ECM production via Klinkhammer et al.
endothelial cells and interaction with PDGFα and PDGFβ receptors on (2018)
macrophages myofibroblasts.
Leukotrienes White blood cells Stimulation of fibroblasts proliferation and production of the Kowal-Bielecka et al.
(LTB4, LTC4, matrix via modulation of the production of cyclic AMP by (2007)
LTD4, LTE4) interaction with G-protein adenylate cyclase.
Profibrotic VEGF Macrophages, fibroblasts, Angiogenesis promotion. Yang et al. (2014)
factors released platelets Facilitates monocyte recruitment and infiltration of fibrotic
from fibroblasts tissues mediated through a VEGF-dependent sinusoidal
permeability, leading either to resolution or promotion of fibrosis.
IL-1 Fibroblasts Facilitates inflammation and fibrosis through autocrine Kelly et al. (2019)
stimulation of IL-1 receptor.
IL-6 Fibroblasts Facilitation of inflammation and fibrosis through binding of IL-6 Kobayashi et al. (2015)
to IL-6Rα receptor, which then associates with the
signal-transducing gp130 protein to facilitate phosphorylation of
the transcription factor STAT-3. Phosphorylated STAT-3
regulates expression of pro-fibrotic genes.
IL-33 Dermal and cardiac fibroblasts Promotion of inflammation and fibrosis by signaling through ST2 Kotsiou et al. (2018)
and activating TGFβ production.
Angiotensin II Macrophages and Promotion of TGFβ mediated heart remodeling. Fibrosis Rosenkranz (2004)
myofibroblasts enhancement via the angiotensin type 1 receptor (AT1).
IGFII Fibroblasts Stimulation of fibrosis through Ghahary et al. (2000)
mannose-6-phosphate/insulin-like growth factor receptor
(M6P/IGFII receptor) in turn activating latent transforming
growth factor β (L-TGF-β).
IGFBP-3 Fibrosis initiation and enhancement by binding IGF-I and ECM Pilewski et al. (2005)
components, inducing the production of extracellular matrix
components such as collagen type I and fibronectin. Inhibit IGF
mediated proliferation (via MEK/ERK and PI3K/AKT).
IGFBP-5 Yasuoka et al. (2009)
Antifibrotic PGE2 Almost all nucleated cells Inhibition of fibroblast proliferation and suppression of collagen Huang et al. (2009)
factors acting production. Promotion of normal fibroblast apoptosis through
on fibroblasts EP2/EP4 signaling and a reduction in the Akt activity.
HGF Fibroblast Prevents fibrosis and induces tissue repair acting through Met Panganiban and Day
receptor and supporting the growth in epithelial and endothelial (2011)
cells, but not in myofibroblasts.
PPAR ligands Expressed in almost all tissues Potent antifibrotic effects, reduction of β-catenin levels. Jeon et al. (2017)
Regulate the fate determination of mesenchymal cell lineage. Vallée et al. (2017)
the contraction of the wound by up to 80%. Granulation tissue phase, the clearance phase, and the ingrowth of granulation
is soft in touch and has a pink color. Granulation is a sign tissue (Figure 3). During the inflammation phase, cells that
of tissue repair; it is formed by three steps: the inflammatory are predominantly involved in the process are monocytes and
neutrophils. The clearance phase is characterized by the release intention occurs by regeneration and scarring. In some cases,
of autolytic enzymes from dying cells as well as enzymes due to abnormal wound healing, keloids or hypertrophic scars
from neutrophils; macrophages also clear necrotic debris. The might occur. In a hypertrophic scar, there is a build-up of extra
final phase is the ingrowth of granulation tissue during which collagen fibers, which results in the elevation of the scar. Fibrillar
granulation tissue is formed. This phase can be divided into two collagen fibers are located parallel to the epidermis with a lumpy
processes: angiogenesis and fibrogenesis (Baum and Duffy, 2011; red scar, and they do not extend beyond the original scarring
Bochaton-Piallat et al., 2016; Alhajj et al., 2020). area. Usually, hypertrophic scars affect younger individuals with
Angiogenesis (neovascularization) is the development of the delayed healing of wounds caused by underlying conditions
blood vessels. Angiogenesis could be the result of sprouting such as infections, and usually, there is an improvement
either from pre-existing blood vessels or from stem cells. There with the treatment. Morphologically keloids are characterized
are a few steps in the angiogenesis from pre-existing blood as eosinophilic, focally fragmented complexes of haphazardly
vessels. The first one involves vessel dilation that is mediated arranged collagen. Also, in comparison with hypertrophic scars,
by NO, and the second step includes an increased vascular one-third of keloids have α–SMA- expressing myofibroblasts. The
permeability that is mediated by the vascular endothelial growth scar tissue in keloids grows beyond the inflammation area, and it
factor (VEGF). The next step is a breakdown of the basement is difficult to treat (Moshref et al., 2010).
membrane and the formation of a vessel sprout. The other step
is the migration of endothelial cells toward chemotactic and
angiogenic stimuli that cause a proliferation of endothelial cells Physiological Injury Healing vs.
and their maturation leading to capillary tube remodeling. The Pathological Fibrosis
final phase of angiogenesis is the accumulation of periendothelial Fibrosis of the organ tissues is caused by parenchymal cell
cells (pericyte) (Papetti and Herman, 2002). destruction (alteration or injury phase); as a result of tissue
Angiogenesis from stem cells develops from endothelial trauma, macrophages become active and enter the damaged
precursor cells (EPC) stored in the bone marrow, and if needed, area. Also, local immune cells create chemokines and cytokines
they migrate to the place of injury (Aldair and Montani, 2010). which activate mesenchymal cells located close to the injury
area. The next step is the initiation of the production of ECM
The Fourth Phase – Healthy Remodeling or and the elevated manufacturing of pro-inflammatory cytokines
Remodeling With Fibrogenesis and angiogenic factors (Weiskirchen et al., 2019). After trauma,
Remodeling (maturation phase) after injury usually takes place cells produce inflammatory mediators that provoke the anti-
from several weeks to months or years and depends on what fibrinolytic coagulation cascade, the first step of which is the
type of tissue is damaged, injury location, and the associated coagulation. During this stage, known as inflammation stage,
comorbidities (infections, arteriosclerosis, vein thrombosis, platelets are activated and form fibrin clots. Next, platelets liberate
nutritional status, diabetes, and some drugs). During remodeling inflammatory chemokines. Then the infiltration of leukocytes
phase, rate of synthesis of collagen by fibroblasts exceeds the rate happens into the injured site, and they excrete profibrotic
at which it is degraded, resulting in continuous increase in the cytokines (TGF-β and IL-13). Neutrophils are typically engaged
amount of collagen. Remodeling includes three steps: functional in the infiltration process earlier than lymphocytes and
recovery, wound contraction and an increased tensile strength of macrophages (Rosales, 2018).
the wound (Cañedo-Dorantes and Cañedo-Ayala, 2019). The The proliferation stage follows the inflammation stage; during
maturation phase is characterized by the formation of scar tissue this stage, fibroblasts become active, and myofibroblasts induce
as well as by the absence of inflammatory cells (neutrophils, and deposit ECM that will be a framework through the tissue
macrophages) and the termination of blood vessel proliferation. regeneration action. The last step is remodeling (Gonzalez
Granulation tissue in the scar is replaced by dense collagen. et al., 2016). In physiological recovery, the extra volume of
The scar initially consists of a provisional matrix that contains ECM is degraded, myofibroblasts and fibroblasts go through
fibrin, fibronectin, and collagen type III, but later on, collagen apoptosis, and inflammatory cells leave the recovered tissues.
type III is replaced by collagen type I (Reinke and Sorg, 2012). On the other hand, the fibrosis process extends inflammation,
The next step is wound contraction, with the main goal being a and myofibroblasts stimulate the elevated accumulation of
reduction of a gap between two cut margins. Myofibroblasts play ECM which leads to the creation of a perpetual fibrotic scar.
a key role during this phase. Figure 4 shows all major processes The contrasting features that distinguish fibrosis from normal
of differentiation, activation or transition of various cells into wound healing are chronic inflammation, the persistence of
myofibroblasts. Collagen type I is responsible for the last step – myofibroblast activity, MMP-TIMP imbalance, and the excessive
an increase in the strength of the wound. The recovery of ∼80% ECM deposition. These differences are very important to be
of the original tissue strength will usually take up to 3 months. understood from the therapeutic point of view because drugs can
Skin wound healing can be subdivided into primary and be prescribed to target these particular molecular disturbances.
secondary unions (Alhajj et al., 2020). By primary union (first Fibroblasts control synthesis and catabolism of collagen as
intention), regeneration occurs with a minimum scaring tissue, well as an increase in collagen amount by MMPs and their
for example, a clean surgical wound. By secondary union inhibitors (tissue inhibitors of TIMPs). Changing the balance
(secondary intention), the wound has the larger tissue defects between these mechanisms will cause the elevation or dropping
with a wide distance between edges; wound healing by secondary of collagen amount inside the injured area. In addition, an
Phases of proliferaon
Inflammatory Clearance phase Ingrowth of granulaon ssue

phase Angiogenesis Fibrogenesis
• NO mediated • Funconal
vessel dilataon recovery
• VEGF mediated • Wound
Recruitment of • Release of vascular contracon
monocytes and autolyc enzymes permeability • Increase in
neutrophils to the from dying cells • Membrane wound strength
wound site • Release of breakdown
enzymes from • Endothelial cell
neutrophils migraon
• Macrophages clear • Pericyte
necroc debris accumulaon
FIGURE 3 | Phases of proliferation and granulation.
Pericytes Resident fibroblasts
MSCs
Myofibroblasts
Mesothelial cells ECM CD34+, CD45+

progenitors
Endothelial cells
Epithelial cells
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.
increasing number of mesenchymal cells will aggravate response. accumulation of collagen. Generally, inflammation stimulates
During the remodeling phase, fibroblasts synthesize collagen at fibrosis. According to some reports, however, fibrosis is not
a higher rate than they degrade it, leading to the continuous always driven by inflammation. This fact clarifies the shortage
of efficacy of anti-inflammatory mediators in the management of with anti-miR-21 oligonucleotides. The peroxisome proliferator-
the fibrotic disease (Wynn, 2007; Kryczka and Boncela, 2015). activated receptors (Pparα) and Mpv17l are two main metabolic
pathways that are key targets for miR-21. Also, miR-21 down-
regulated inhibitors of angiogenesis and migration, especially
Fibrosis Prevention and Treatment the RECK (the reversion-inducing cysteine-rich protein with
Options Kazal motifs) and the atypical matrix metalloproteinase (MMP)
Prevention strategies for the development of fibrosis are very inhibitor that led to the enhanced MMP activity in kidney
important in the modern world because life expectancy and injury (Chau et al., 2012). As a result of the administration
the patients’ quality of life are expected to rise gradually. of oligonucleotides that silenced miR-21, a reversal of the
When patients are aware of avoidable risk factors for this deleterious action of miR-21 in kidney injury was noted. Some
condition, they, for example, should quit smoking to prevent studies demonstrated a significant effect of miR-21 on pulmonary
the development of pulmonary fibrosis and should treat all and cardiac fibrosis (Thum et al., 2008).
acute diseases in time to prevent the development of chronic In multi-component therapy, several approaches are
conditions. There are unavoidable factors such as genetics, the combined, with numerous ingredients acting on numerous
existing comorbidities (diabetes mellitus, herpes virus infection), targets. In fibrosis, there are multiple pathological pathways
the environmental exposures, air pollution as well as chronic and multi-component drugs that are able to modulate these
use of some medications that also have to be considered pathways and create synergistic effects. In the Table 3, single and
(Zaman and Lee, 2018). multi-component medications used nowadays in the treatment
Anti-inflammatory drugs are widely used to manage fibrosis of fibrosis are summarized (Li et al., 2017).
due to a strong connection between inflammation and fibrosis Only nintedanib and pirfenidone have been approved by FDA
(Suthahar et al., 2017; Lands and Stanojevic, 2019; Simon et al., for the treatment of fibrosis, particularly of IPF, and ruxolitinib
2019). As a result of better understanding of the pathology of has been approved by FDA for the treatment of myelofibrosis;
fibrosis, molecular targets of this condition and modern drugs other medications are still experimental, and some of them are
affecting it have been recently discovered. A single-component undergoing clinical trials the results of which might help improve
medication is characterized by the presence of a single the understanding of the fibrosis pathway.
component that can target either extracellular or intracellular Nintedanib medication is a small molecule kinase inhibitor
factors. The main extracellular targets are MMPs, growth factors, that reduces the proliferation and migration of lung fibroblasts.
TNF. Most of the drugs targeting intracellular factors are small Nintedanib inhibits receptor tyrosine kinases (RTKs), for
molecules; they can easily translocate inside the cytoplasm instance, FGFR1-3, VEGFR1-3, Fns-like tyrosine kinase-3
compared to other large molecules, like monoclonal antibodies. (FLT3), PDGFR α and β. Also, this drug inhibits kinase
There are four categories of intracellular factors that signaling pathways. Its main side effects are nausea, diarrhea,
can be targeted by anti-fibrotic medicine: nuclear receptors, and liver dysfunction (Wind et al., 2019; Valenzuela et al.,
enzymes, other proteins, and epigenetic factors (Li et al., 2020). In clinical practice, a long-term use of nintedanib is
2017). The antifibrotic medications suppress kinases located still discussed. Research in this area will help improve patient
in the cytoplasm, and moreover, they inhibit the translocation outcomes (Valenzuela et al., 2020). Pirfenidone treatment mainly
of transcription factors responsible for the expression of reduces fibroblast proliferation and causes the inhibition of
profibrotic genes. collagen synthesis and down-regulation of profibrotic cytokines.
Epigenetic regulators represent a very specific category of As a result of inhibition, it causes the suppression of TGF-
anti-fibrotic treatment. The main targets of epigenetic-based β2 mRNA levels and TGF-β2 protein and the suppressed
management of fibrosis are microRNAs (miRNAs). Anti-miRs – expression of the TGF-β pro-protein convertase furin. Also,
are miRNA oligonucleotides that are able to complementary this drug decreases the MMP-11 protein levels. It should be
bind to miRNAs involved in fibrosis and neutralize them when noted that pirfenidone has some severe side effects such as
deposited inside the cell. miRNAs like let-7, miR-21, miR-29, photosensitivity, nausea, stomach pain and many others that
miR-155 play an important role in fibrosis, particularly in TGF- may lead to medication intolerance and discontinuation (Hughes
β control. Let-7 and miR-29 are antifibrotic; in contrast, miR-21 et al., 2016; Margaritopoulos et al., 2016; Moran-Mendoza et al.,
and miR-155 are profibrotic, and their expression will rise during 2019). Ruxolitinib is widely used in myelofibrosis treatment.
the fibrosis. On the other hand, the decreased expression of miR- This drug is a kinase inhibitor that is selective for JAK1 and
29 in systemic sclerosis (SSc) fibroblasts leads to the increased 2. The main role of these kinases is the regulation of growth
levels of type I and III collagen. The reduction of miR-29 was factor signaling and cytokine release. The known side effects
noted in the fibrotic reaction in the lungs, heart, and kidneys. of this medicine are anemia, thrombocytopenia, increased liver
IL-4, TGF-β, and PDGF-B reduced the level of miR-29 in SSc enzymes, and diarrhea (Elli et al., 2019).
fibroblasts as well as in the bleomycin-induced model of skin
fibrosis (Maurer et al., 2010; Harmanci et al., 2017). According
to another study, miR-21 was highly elevated in animal and The Role of Cannabinoids and Cannabis
human models of transplant kidney nephropathy. MiR-21−/− in Inflammation and Fibrosis
mice experienced less interstitial fibrosis in response to kidney Recently, the ECS has received a significant attention from
injury; this was pheno-copied in wild-type mice that were treated mainstream medical professionals, being viewed as an important
TABLE 3 | Single- and multi-component medications targeting fibrosis factors.
Group Target or Mechanism of action Drug name Disease Reference/trial

mechanism identifier
type
Single-component medications targeting extracellular factors

Growth factor Extracellular TGF-β, inhibitor Pirfenidone IPF Margaritopoulos et al.
TGF-β signaling (2016)
PDGF/VEGF PDGFR, antagonist Imatinib SSc, nephrogenic NCT00677092
systemic fibrosis, IPF NCT00613171
NCT00131274
VEGFR/PDGFR, Nintedanib Scleroderma, IPF NCT02597933
antagonist NCT01335464
TNF TNF, inhibitor Talidomide IPF NCT00162760
TNF, inhibitor Etanercept IPF NCT00063869
TNF, inhibitor Belimumab SSc NCT01670565
Cytokines Interleukin IL-1R1, antagonist Anakinra Cystic fibrosis Iannitti et al. (2016)
IL-1 βR, antagonist Rilonacept SSc NCT01538719
Interferon IFN-γR, stimulant Actimmune IPF, cystic fibrosis, liver NCT00047658
fibrosis NCT00043303
NCT00043316
MMP/TIMP MMP/TIMP MMP/TIMP, inhibitor Marimastat Liver fibrosis de Meijer et al. (2010)
Other proteins and peptides Endothelin ET-1 receptor, Macitentan IPF NCT00903331
antagonist
Bosentan IPF NCT00070590
NCT00319696
NCT01395732
Ambrisentan IPF, SSc NCT00879229
NCT01051960
Angiotensin II AT1 receptor, Losartan Cystic fibrosis, Liver NCT00298714
antagonist fibrosis NCT03206788
GPCR Prostacyclin receptor, Iloprost SSc NCT00109681
agonist
Treprostinil IPF, SSc NCT00703339
NCT00775463
Single-component medications targeting intracellular factors
Enzymes mTOR mTORC1/2, inhibitor Rapamycin (Sirolimus) Renal intestinal fibrosis NCT01079143
JAK-STAT JAK1/JAK2, inhibitor Ruxolitinib Myelofibrosis NCT00952289
PI3K-Akt Akt, inhibitor Omipalisib IPF NCT01725139
MAPK MAPK, inhibitor MMI-0100 IPF, cardiac fibrosis Xu et al. (2014)
NF-kB IKK, inhibitor IMD-1041 Cardiac fibrosis Tanaka et al. (2012)
Nuclear receptors PPAR PPAR-γ, agonist Rosiglitazone Liver fibrosis NCT00492700
Other proteins Intracellular SMAD2/3, inhibitor Pirfenidone IPF, SSc NCT00287729
TGF-β signaling NCT01933334
SMAD3/4, inhibitor Pentoxifylline Skin fibrosis NCT00001437
SMAD3, inhibitor SiS-3 Renal fibrosis, liver NCT00686881
Glycyrrhizin fibrosis Meng et al. (2015)
Epigenetics miRNA miR-21, inhibitor Anti-miR-21 IPF, renal fibrosis Liu et al. (2010)
Chau et al. (2012)
Multi-component drugs
TGF-pc/MMP- Fuzhenghuayu capsule Liver fibrosis NCT00854087
2c (FZHY) NCT02241616
TNF-α/TGF-β Danggui-Buxue-Tang IPF Lv et al. (2012)
(DBTG)
TGF-β, transforming growth factor-β; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor;
VEGFR, vascular endothelial growth factor receptor; TNF, tumor necrosis factor; IFN-γR, interferon-γ receptor; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of
metalloproteinase; ET-1 receptor, endothelin-1 receptor; AT1 receptor, angiotensin II receptor type 1; GPCR, G protein-coupled receptor; mTOR, mechanistic target of
rapamycin; mTORC1, mechanistic target of rapamycin complex 1; JAK-STAT, janus kinase/signal transducers and activators of transcriptions; PI3K-Akt, phosphoinositide
3-kinase/protein kinase B; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor kappa-light –chain- enhancer of activated B cells; IKK, I-kappa B kinase;
SMAD3, mothers against decapentaplegic homolog 3.
therapeutic target for many pathological conditions. Human Cannabinoids as Anti-inflammatory Agents
physiology significantly depends on a proper function of According to previous reports, some of the cannabinoids can
this system. The ECS has been established as an important be used as anti-inflammatory agents (Zurier and Burstein,
homeostatic regulator. It affects almost all functions of the body. 2016; Wang et al., 2020). Currently in medical practice, these
It consists of endocannabinoids (2-AG, AEA), their metabolic substances have little documented negative effect on patients
enzymes and receptors, including cannabinoid receptors 1 in comparison with other drugs. Cannabinoids have other
(CB1), cannabinoid 2 (CB2), transient receptor potential mechanisms of action on inflammation in comparison with
channels of the vanilloid subtype 1 and 2 (TRPV1, TRPV2), nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit
G protein-coupled receptors 18, 55, 119 (GPR18, GPR55, the activity of cyclooxygenase enzymes, prostaglandins (Zurier
GPR119) (Laezza et al., 2020). Cannabinoid receptors are highly and Burstein, 2016). Recently, it has been discovered that
expressed in cells involved in two subtypes of immunity, cannabinoid receptor signaling regulates the proliferation and
adaptive and innate. For example, CB1 and CB2 receptors function of fibroblasts which are crucial cells in scar formation
are expressed in the natural killer cells, macrophages, T (Nagarkatti et al., 2009). By suppressing inflammation, they
and B cells (Chiurchiù, 2016). In general, activation of the may stop the progression of repair by scarring. It has been
CB2 receptor leads to anti-inflammatory effects. Since the shown that cannabinoids and cannabis extracts suppress the
expression of CB1 receptors is lower in the immune cells pro-inflammatory cytokines IL-2, IL-1β, TNF-α, IFN-γ, IL-12,
than the expression of CB2 receptors, their function in the IL-8, IL-6 in different cell lines and animal models. Due to
immune system still remains controversial (Turcotte et al., 2016). this, the inflammatory process will be prominently inhibited
CB2−/− mice exhibit abnormalities in the development of T (Nagarkatti et al., 2009).
and B cells (Ziring et al., 2006). Cannabinoids, mainly by One of the anti-inflammatory mechanisms of cannabinoids is
modulating the expression of ECS receptors induce apoptosis through the regulation of mitochondrial homeostasis. CBD has
of immune cells, and inhibit their proliferation; suppress pro- been shown to alleviate cerebral ischemia in rats by reducing
inflammatory cytokines production, and induce T-regulatory brain oedema, blood-brain barrier permeability, infarction size,
cells (Nagarkatti et al., 2009). The imbalance in the ECS and neurological deficit. This effect was due to the increased
can significantly impact the proper functioning of the whole expression of Na+ /Ca2+ exchanger proteins (Khaksar and
organism, including fibrosis and inflammation processes. For Bigdeli, 2017). When blood flow is restored in the ischemic
example, the activation of the CB1 receptor leads to fibrogenesis, area, it causes inflammation and oxidative-stress-related injury
while the enhancement of the CB2 receptor inhibits fibrosis in the affected area. CBD has demonstrated a neuroprotective
progression (Mallat et al., 2011). In animal models, it was effect in oxygen–glucose-deprivation/reperfusion in vitro model
demonstrated that the deletion of CB1 caused an improvement by reducing the oxidative stress, improving mitochondrial
of liver fibrosis, whereas CB2 deletion resulted in an elevated bioenergetics and modulating the glucose metabolism (Sun et al.,
amount of collagen accumulation and an increased inflammation 2017). In contrast, THC treatment of the trophoblast cell line,
(Patsenker and Stickel, 2016). Concerning inflammation, the HTR8/SVneo, showed a reduction in mitochondrial respiratory
use of CB2 receptor agonists was documented to inhibit function and membrane potential. This data suggested that THC
the infiltration of inflammatory cells into liver tissue. In can cause dysfunction of mitochondria (Walker et al., 2021).
addition, CB2 receptor knockout mice had the more profound When THC effect was evaluated on mitochondria, extracted
inflammation and damage to the liver than wild-type mice from the rat brain, similar results were obtained: it enhanced
(Batkai et al., 2007). oxidative stress and induced mitochondrial dysfunction in the
Cannabis is widely known as a plant with psychoactive brain (Wolff et al., 2015).
properties. It includes over 500 compounds such as different Cannabis extracts were even proposed to be used for
cannabinoids, terpenes, terpenoids, fatty acids, and flavonoids. prevention and treatment of COVID-19. Significant inhibitory
Cannabinoids (known as phytocannabinoids in contrast to effects on the key receptor protein Ace2 required for SARS-Cov2
endocannabinoids) act via the ECS. The most abundant are virus entry in the gateway entry tissues was found in response to
cannabidiol (CBD) and 19-tetrahydrocannabinol (19-THC); several cannabis extracts (Wang et al., 2020). Similarly, several
they are the most studied cannabinoids with numerous other extracts were found to be potent inhibitors of major
documented medicinal properties (Zurier and Burstein, pro-inflammatory molecules responsible for severe COVID-19
2016; Lafaye et al., 2017). The uniqueness of the effect of progression (Wang et al., 2020).
cannabis extracts is in entourage effect. Often, but not always, It was also shown that cannabis users living with HIV have
cannabis extracts have more profound effects on various lower neuroinflammation. This was confirmed by demonstrating
disease and conditions than isolated cannabinoids (Kovalchuk that marijuana users had lower levels of CD16+ monocytes and
and Kovalchuk, 2020). This is due to modifying effects of inducible protein 10 (IP-10) compared to HIV-infected patients
minor cannabinoids, terpenes and other molecules that non-cannabis users (Rizzo et al., 2018).
frequently act as amplifiers, acting on the same receptors.
Looking at the enormous varieties of cannabis cultivars Cannabinoids as Anti-fibrotic Agents
nowadays, it is clear that research in this field should A lot of research has already been done, and currently many
continue to discover new possibilities of fibrosis treatment studies are undergoing on the use of endo-, synthetic, and
(Russo, 2019). phytocannabinoids in the fibrosis field. In one in vivo study
where a mouse model of type I cardiomyopathy was used, it MMP2, MMP9, and TIMP1. These effects were mediated through
was demonstrated that CBD treatment diminished the diabetes- the PPARα mechanisms (McVicker and Bennett, 2017).
associated cardiac fibrosis. A significant decrease of collagen Synthetic cannabinoids were also shown to be beneficial for
deposition and the expression of profibrotic genes like MMP- fibrosis treatment. An in vitro study performed on pulmonary
2, MMP-9, TGF-β, connective tissue growth factor, fibronectin fibroblasts demonstrated that JWH133, a CB2 receptor agonist,
andcollagen-1 were noted (Montecucco and Di Marzo, 2012). suppressed the collagen type I and α-SMA and inhibited the
Liver fibrosis is a usual complication of many long-lasting proliferation and migration of fibroblasts. These effects were
liver illnesses such as viral hepatitis B and C, non-alcoholic reversed by the use of a CB2 receptor antagonist, SR144528.
steatohepatitis, drug-induced liver injury, alcohol abuse, and In vivo studies on bleomycin-induced lung fibrosis in mice,
autoimmune conditions. In long-lasting liver damage, the showed that JWH133 decreased the lung density, and the
activated hepatic stellate cells (HSCs) and myofibroblasts are fibrotic score and histological results illustrated the suppression
the main contributors to the development of liver cirrhosis of the collagen accumulation and inflammatory response. In
and hepatocellular cancer (Fu et al., 2011). An in vitro both models, this particular synthetic cannabinoid inhibited
study performed on HSCs documented that CBD induced the the crucial pathway of fibrogenesis, TGF-β1/Smad2 (Fu et al.,
programmed cell death of these cells (Lim et al., 2011). This 2017). WIN-55,212, a nonselective CB1 and CB2 receptor agonist
effect was independent of cannabinoid receptors and was the as well as JWH133 were assessed on the mouse model of
result of endoplasmic reticulum stress induction. In addition, systemic sclerosis. They prevented the development of dermal
CBD enhanced the pro-apoptotic pathway IRE1/ASK1/c-Jun and pulmonary fibrosis and inhibited the proliferation of
N-terminal kinase, which resulted in HSCs death. This CBD- fibroblasts. CB2−/− mice developed a significantly enhanced
induced programmed cell death of activated HSCs was confirmed skin and lung fibrosis compared with CB2+/+ mice, indicating
in vitro in human, mouse and rat cell lines, but not in the significant influence of the CB2 receptor on fibrosis development
quiescent cell lines. The well-known fact that the activated HSCs (Servettaz et al., 2010). Rimonabant, a CB1 receptor antagonist,
play a crucial role in the development and continuation of liver was assessed on rat models of liver cirrhosis induced by
fibrosis supports the fact that cannabis extracts might be turned carbon tetrachloride. Fibrosis was prominently suppressed by
into promising antifibrotic drugs as they lead to the selective the use of this synthetic cannabinoid in rats compared with
apoptosis of activated HSCs. The results of this study are very rats in the vehicle group. Rimonabant downregulated the
encouraging for further investigation of CBD in vivo (Lim et al., fibrogenic (TIMP-1, TGF-β, MMP13, MMP2, MMP9, MMP1,
2011). In addition, a meta-analysis of nine studies performed MMP8) and inflammatory mediator (TNF-α, MCP-1) genes. In
on 5,976,026 patients concluded that marijuana did not elevate addition, Rimonabant treatment induced a prominent increase
the prevalence or progression of liver fibrosis in patients with in the expression of the CB2 receptor (Giannone et al.,
hepatitis C or hepatitis C HIV co-infection (Hosein Mohimani 2012). Another study demonstrated that chronic stimulation of
et al., 2017). Also, it was noted that marijuana users had a CB2 receptor with selective CB2 receptor agonist, JWH-133,
reduced prevalence of non-alcoholic fatty liver disease (NAFLD). leads to regression of fibrosis in cirrhotic rats. This selective
Furthermore, these patients consumed more sodas and alcohol, agonist suppressed the inflammatory infiltrate, decreased fibrosis,
therefore the healthy lifestyle was not a cause of the reduced lowered the number of activated hepatic stellate cells, and
prevalence of NAFLD. This effect might be induced by reducing improved arterial pressure in comparison to the vehicle group.
fat depositions via omega-3 fatty acids and the impact of CBD on In addition, JWH-133 reduced levels of α-SMA and collagen
insulin sensitivity (Hosein Mohimani et al., 2017). and elevated levels of MMP-2 in the liver tissue of rats with
Concerning the effect of THC, it has been shown that it cirrhosis in comparison with untreated rats with cirrhosis.
also inhibits the proliferation of liver myofibroblasts and stellate This data provided promising results for the possibility to use
cells via CB2 receptors and leads to their programmed cell selective CB2 receptor agonists as a treatment modality of
death. Due to this, THC may also possess antifibrotic properties hepatic fibrosis in humans (Muñoz-Luque et al., 2008). Another
(Tam et al., 2011). study tested the effect of a selective CB2 receptor agonist,
The endocannabinoid AEA also demonstrated the anti- AM1241, on myocardial fibrosis post-myocardial infarction
fibrogenic features by suppressing the proliferation of HSC and in mice. The echocardiography results demonstrated that
induction of necrosis. The elevated AEA levels were documented AM1241 significantly enhanced cardiac function; downregulated
in cirrhotic patients, which might be a response to fibrosis. This expression of collagen I, collagen III, TIMP-1, and plasminogen
endogenous cannabinoid can trigger the topical inflammatory activator inhibitor (PAI)-1. When primary cardiac fibroblasts
response and systemic dilatation of vessels, therefore the were exposed to hypoxia and serum deprivation to simulate
opportunity for fibrosis treatment was restricted (Parfieniuk and ischemia, AM1241 was able to reduce α-SMA, collagen I
Flisiak, 2008). Another endocannabinoid, 2-AG, was considered and collagen III; this effect was partially abrogated by the
as a fibrogenic agent. When used in higher doses in vitro on HSC, Nrf2 siRNA transfection. Moreover, the CB2 receptor agonist,
it activated fibrosis via the membrane cholesterol-dependent AM1241, activated and enhanced the translocation of Nrf2 to
mechanism (Tam et al., 2011). Another endogenous cannabinoid, the nucleus and inhibited the TGF-β1/SMAd3 pathway. These
oleoylethanolamide (OEA), was used in a mouse model of hepatic data suggest that activation of the CB2 receptor might be one
fibrosis and showed the inhibition of collagen deposition and of the key targets to combat heart fibrosis after myocardial
suppression of collagen type I and III gene expression, α-SMA, infarction (Li et al., 2016). The chronic peripheral pharmaceutical
TABLE 4 | Anti-fibrotic effect of cannabinoids.
Compound The mechanism of action References
Endocannabinoids
AEA Suppressing the proliferation of HSCs and induces their Parfieniuk and Flisiak (2008)
necrosis
2-AG Generally considered as a fibrogenic agent, however, it is Tam et al. (2011)

able to suppress fibrosis via the membrane
cholesterol-dependent mechanism.
OEA The inhibition of collagen deposition and suppression of McVicker and Bennett
collagen type I and III gene expression, α-SMA, MMP2, (2017)
MMP9, and TIMP1. These effects were mediated through
the PPARα mechanisms.
Phytocannabinoids
CBD The apoptosis induction of HSCs as result of the induction Lim et al. (2011)
of endoplasmic reticulum stress and the enhancement of
the pro-apoptotic pathway IRE1/ASK1/c-Jun N-terminal
kinase.
THC The inhibition of miofibroblast proliferation and stellate cells, Tam et al. (2011)
the induction of their apoptosis via CB2 receptors.
Synthetic cannabinoids
JWH-133 The suppression of collagen type I and α-SMA, inhibition of Fu et al. (2017)
fibroblast proliferation and migration. The down-regulation Muñoz-Luque et al. (2008)
of the TGF-β1/Smad2 pathway.
Rimonabant The suppression of expression of fibrogenic mediators Giannone et al. (2012)

(TIMP-1, TGF-β, MMP13, MMP2, MMP9, MMP1, MMP8,
TNF-α, MCP-1)
AM1241 The downregulation of expression of collagen I, collagen III, Li et al. (2016)

TIMP-1, and plasminogen activator inhibitor. The inhibition
of the TGF-β1/SMAd3 pathway.
SLV319 The suppression of glucose transporter 2; reduction in Hinden et al. (2018)

glucose reabsorption.
JD5037 The suppression of glucose transporter 2; reduction in Hinden et al. (2018)

glucose reabsorption.
Lenabasum Stimulating PPAR-γ signaling Gonzalez et al. (2012)
blockage of CB1 receptor (by SLV319 or JD5037 selective CB1 of bleomycin-induced skin fibrosis in mice and suppressed its
receptor antagonists) or genetic inactivation of CB1 receptors progression. In addition, it inhibited collagen synthesis by skin
in the renal proximal tubule cells reduced kidney inflammation, fibroblasts obtained from patients with scleroderma. These effects
suppressed tubulointerstitial fibrosis, and diminished diabetic- were achieved by stimulating PPAR-γ signaling (Gonzalez et al.,
induced changes in the kidneys in mice. Also, the downregulation 2012). Lenabasum has been shown to have an anti-inflammatory
of the CB1 receptor suppressed glucose transporter 2, which capacity by directly affecting both arachidonic acid pathways
resulted in reduced glucose reabsorption. These data supported (Burstein, 2021). Lenabasum was the only synthetic cannabinoid
the fact that peripheral CB1 receptor antagonists might be useful studied in human fibrotic diseases. A Phase II, randomized,
in treating patients with diabetic nephropathy (Hinden et al., placebo-controlled trial in adults suffering from systemic sclerosis
2018). A synthetic analog of THC, ajulemic acid (lenabasum), showed promising results (NCT03398837); a high improvement
being a CB2 agonist, significantly prevented the development rate on the immunosuppressant therapy background, and high
improvement on mycophenolate that has an anti-fibrotic activity

and prevents pulmonary deterioration in pulmonary fibrosis was Alteraon/
Injury
observed. Unfortunately, the primary endpoint was not met injury
during this trial (Spiera et al., 2021). Table 3 summarizes type of
cannabinoids and their mechanism of action (Table 4).
Epithelial or/and endothelial cells
Acvaon of platelets and formaon of fibrin clot

Into Potential Mechanisms of
Anti-fibrotic Effects of Cannabinoids –
Role of MicroRNAs Release of chemical mediators Release of immune cells
• IL-2 • T cell
The mechanisms of anti-fibrotic effects of cannabinoids are likely • IL-6, • B cell
very diverse. Cannabinoids may target all steps of normal and • IL-1β, • Neutrophil
abnormal wound healing, as shown on Figure 5. • IFN-γ, • Macrophage
THC/CBD
Recent reports demonstrate the role of miRNAs in regulation • TNF-α,
• TGF-β,
of cannabinoid receptors and anti-fibrotic effect of cannabinoids. • NF-kB
miRNAs like miR-30b-5p, miR-21, miR-155, miR-146a, miR- Exudaon
141, and miR-222 appear to be pro-inflammatory, while
Vasodilataon Increased Chemotaxis of Leukocytosis
miRNAs like miR-187, miR-149, miR-145, and miR-99b are anti- capillary neutrophils,
inflammatory. permeability lymphocytes Migraon
miR-30b-5p was found to be involved in CB1-mediated and monocytes
NLRP3 inflammasome activation. The study performed on Marginaon
mice with liver injury induced by carbon tetrachloride (CCl4) Exudate
THC/CBD
or methionine-choline-deficient, and high fat (MCDHF) diet formaon Diapedesis
showed that there is a relationship between CB1 receptor and
Nod-like receptor family pyrin domain containing 3 (NLRP3) Phagocytosis
Angiogenesis
inflammasome in liver inflammation. The expression of the of pathogen
CB1 receptor was increased in hepatic tissue of mice with liver Proliferaon
injury. CB1 receptor agonist, arachiodonyl-20 -chloroethylamide, Wound contracon Chronic injury
enhanced expression of NLRP3 inflammasome and its activation and re-epithelizaon or inflammaon
in macrophages. AM281, a CB1 receptor antagonist, inhibited
Connuing
NLRP3 expression and activation of the inflammasome and myofibroblast
reduced hepatic inflammation in CCl4- and MCDHF-treated Cannab acvaon
mice. When miR-30b-5p agomir was administered, it targeted MMP-TIMP inoids
balance MMP-TIMP
NLRP3 and mitigated liver inflammation. These results suggested imbalance
that CB1/miR-30b-5p axis is able to modulate the activation of
Excessive ECM
NLRP3 inflammasome and expression of NLRP3 in macrophages deposion
in liver inflammatory disease (Yang et al., 2020).
Cannabinoids can alter the expression of miR-155, a Regeneraon of Fibroc healing
master regulator of inflammation (Mahesh and Biswas, 2019). damaged ssues
Administration of selective CB2 receptor agonist AM1241
significantly reduced expression of TLR4, α-SMA, TGF-β1, FIGURE 5 | Effect of cannabinoids on various stages of wound healing in view
of preventing/treating fibrosis. During the first stage of wound healing
miR-155, p65 NFkB, TNF-α, IL-6, IL-1β and vimentin genes cannabinoids are responsible for inhibiting immune response by suppressing
caused by thioacetamide. Moreover, it significantly upregulated the release of immune cells into the injury cite and by inhibiting Th1 response
E-cadherin, glutathione content, and superoxide dismutase. This and main pro-inflammatory cytokines (IL-2, IL-6, IL-1β, IFN-γ, TNF-α, TGF-β,
study showed that AM1241 reduces fibrosis, by activating the NF-kB) (Watzl et al., 1991; Srivastava et al., 1998; Dinu et al., 2020). During
exudation stage, cannabinoids inhibit the angiogenesis (Wietecha and
CB2 receptor, and inhibiting TLR4/miR-155/NFκB p65 pathway
DiPietro, 2013). Cannabinoids also actively contribute to the proliferation stage
(Ali et al., 2021). by suppressing chronic inflammation (Costa et al., 2007; Gallily et al., 2018),
Chronic administration of THC significantly increased the myofibroblast activation (Garcia-Gonzalez et al., 2009), the excessive
expression of anti-inflammatory miRNAs including miR-187, deposition of ECM components (Garcia-Gonzalez et al., 2009) and
miR-149, miR-145, miR-99b, miR-24, and miR-10a dysregulated normalization of TIMP-MMP imbalance (Garcia-Gonzalez et al., 2009).
by acute infection with Simian Immunodeficiency Virus (SIV).
THC administration also reduced viral load, gastrointestinal
inflammation, and the overall disease progression (Chandra miRNAs, including pro-inflammatory miRNAs miR-21, miR-
et al., 2015). Another study, performed on rhesus macaques 141 and miR-222 and miR-204, that directly targets matrix
with chronic SIV infection with an intention to cause fibrosis, metalloproteinase 8 (MMP-8), an enzyme that degrades collagen
showed that THC prevented fibrosis and upregulated ten (Kumar et al., 2019). In addition, THC inhibited proliferation
TABLE 5 | A comparison of target molecules in treatment of fibrosis using modern therapy vs. cannabis treatment.
A single-component medication: Cannabis
The mechanism of action of asingle-component medication vs. cannabis
• TGF-β inhibitor (Pirfenidone) • TGF-β inhibitor

• PDGFR antagonist (Imatinib) • TNF inhibitor
• TNF inhibitor (Talidomide, Etanercept, Belimumab) • MMP/TIMP inhibitor
• IL-1 antagonist (Anakinra, Rilonacept)
• IFN-γ stimulant (Actimmune)
• MMP/TIMP inhibitor (Marimastat)
• mTOR inhibitor (Rapamycin)
• JAK-STAT inhibitor (Ruxolitinib)
• PI3K-Akt inhibitor (Omipalisib)
• MAPK inhibitor (MMI-0100)
• NF-kB inhibitor (IMD-1041)
• miR-21 inhibitor (Anti-miR-21)
The mechanism of action of a multi-component medication vs. cannabis
A multi-component medication: Cannabis
• TGF-pc/MMP-2c inhibitor (Fuzhenghuayu) • TGF-β1/Smad2 inhibitor

• TNF-α/TGF-β inhibitor (Danggui-Buxue-Tang)
and activation of T cells, suppressed PD-1 expression, and IFN-γ inhibitor. THC was able to reverse this miRNA imbalance.
elevated the percentage of anti-inflammatory macrophages Moreover, when primary cells from these mice were transfected
in intestinal tissue. These results suggest that THC is an with miR-21 inhibitor or miR-29b mimic, the expression of
important modulator of miRNA expression and can suppress SMAD7 increased, and the expression of IFN-γ decreased
intestinal inflammation and may prevent lymph node fibrosis (Sido et al., 2016).
(Kumar et al., 2019). In another study, when C3H/Hej mice were administered
In another study, lipopolysaccharide (LPS) was used to staphylococcal enterotoxin B (SEB), it caused an acute mortality;
stimulate the BV-2 microglial cells, and CBD had a much more in contrast, mice that received THC had a 100% survival rate
significant effect than THC on the expression of cluster miRNAs and did not show any respiratory distress signs, hunched posture,
(Juknat et al., 2019). While LPS increased the expression of many or fur ruffling. In addition, the THC administration significantly
pro-inflammatory miRNAs, including miR-155, miR-146a, and reduced the vascular leak in comparison to the staphylococcal
miR-21, associated with Toll-like receptor (TLR) and NF-κB enterotoxin B exposure group. The staphylococcal infection
signaling, the CBD suppressed the expression of miR-155 and caused the induction of miRNA-17-92 cluster, including miR-
miR-146a. Moreover, it was demonstrated that LPS modulates 18a, which targeted the inhibitor of PI3K/Akt pathway, leading
the Notch signaling pathway by increasing the mRNA expression to suppression of T regulatory cells (Rao et al., 2015).
of Notch ligand Dll1. CBD and THC were able to reduce the Another study showed that THC administered in post-
expression of this ligand. Since the CBD+LPS group increased the staphylococcal enterotoxin B exposure protected mice from acute
expression of miR-34a and downregulated the expression of its respiratory distress syndrome and toxicity. THC significantly
target gene Dll1, it was suggested that miR-34a could be involved downregulated let7a-5p and miR-34-5p, which target SOCS1,
in the Notch signaling pathway modulation and, as a result, in FoxP3, NOS1, and CSF1R as well as inhibited the pro-
reducing inflammation (Juknat et al., 2019). inflammatory cytokines, such as TNF-α and IFN-γ. This
Cannabidiol was demonstrated to trigger apoptosis in human study suggested that THC can alter miRNA expression in the
neuroblastoma cell lines by downregulation of let-7a expression lungs, suppress the cytokine storm, and as a consequence,
and, as a consequence, upregulation of caspase-3 and several might cause mitigation of SEB-mediated pulmonary injury
growth arrest genes. In addition, CBD upregulated the expression (Mohammed et al., 2020).
of has-mir-1972 and caused decreased expression of BCL2L1 and A combination of THC plus CBD suppressed
SIRT2 genes (Alharris et al., 2019). neuroinflammation in murine experimental autoimmune
Yet another study showed that THC treatment can suppress encephalomyelitis (EAE) model and suppressed Th1 and Th17
the activation of Th1/Th17 lineage commitment via regulation of cells via modulating miRNA expression. In addition, this
miRNA expression (Sido et al., 2016). When C57BL/6 mice with combinational treatment reduced levels of CD4+ T cells and
delayed-type hypersensitivity were treated with THC, oedema pro-inflammatory molecules such as TNF-α, IL-1β, IL-6, IFN-γ,
and immune cells infiltration subsided at the place of antigen IL-17, and TBX21) while elevating anti-inflammatory molecules
rechallenge. Delayed-type hypersensitivity caused an increased (IL-4, IL-10, TGF-β, STAT5b, and FoxP3). Microarray analysis of
expression of miR-21 and inhibition of miR-29b; miR-21elevates miRNA of CD4+ T cells showed that THC+CBD administration
the Th17 differentiation via inhibiting SMAD7, while miR-29b is significantly inhibited miR-122-5p, miR-27b-5p, miR-155-5p,
miR-150-5p, miR-146a-5p, miR-31-5p, miR-21a-5p and pathways may give us a chance in the future to discover
upregulated miR-7116 and miR-706-5p (Al-Ghezi et al., 2019). an effective antifibrotic treatment. Many studies have been
miR-29a appears to be one of the regulators of response performed to understand the molecular mechanisms, the cellular
to cannabinoids. miR-29a diminishes diabetic nephropathy via basis, and the most prominent characteristics of fibrosis in
modulation of CB1 signaling. Upregulated expression of the CB1 human organs. Molecules like TNFα play a key role in the
receptor, TNF-α, IL-6, IL-1β, collagen IV, and downregulated establishment of inflammation and pathogenesis of fibrosis. At
expression of PPAR-γ was noted in streptozotocin-induced the same time, TNFα may be used a therapeutic agent that
diabetic mice. In contrast, overexpression of miR-29a in mice can resolve the established pulmonary fibrosis (Redente et al.,
negatively regulated CB1 receptor, blocking upregulation of 2014), further confirming that we do not have a clear picture of
pro-inflammatory and fibrogenic compounds, and substantially mechanisms and pathways of fibrosis.
decreasing kidney hypertrophy. The overexpression of miR-29a In most tissues and organs, the fibrosis mechanisms are
also renewed PPAR-γ signaling. These data demonstrated that similar, but the regeneration and regression processes are
interaction among miR-29a, CB1 receptor, and PPAR-γ signaling different across organs and tissues. Mainly this diversity is due to
plays a significant role in protecting renal tissue from developing the difference in the regenerative capacity of each tissue or organ
fibrosis (Tung et al., 2019). (Friedman, 2015).
Based on reports presented in this review, we propose
Cannabis and Cannabinoids May that single cannabinoids and components of cannabis extracts
Replace the Known Therapies for can positively interact with the key profibrotic factors
Fibrosis and pathways. In comparison with modern antifibrotic
medications, cannabinoids have fewer negative effects on
Due to the lack of effective therapies for fibrosis, new more
patient’s health.
effective and modern therapies with less side effects need to be
We conclude that modulation of ECS should be a modern
developed. The currently used drugs suppress the fibrogenetic
approach for the treatment of different fibrotic conditions.
pathways and reduce the progression of fibrosis. Similarly,
This aspect of treatment has not been sufficiently studied.
cannabis extracts can also affect key profibrotic factors and
More detailed research should be done to find a patient-
pathways. Cannabinoid signaling regulates the proliferation and
oriented treatment and improve patients’ quality of life.
function of fibroblasts which are crucial cells in scar formation.
It would be very encouraging to find the curative option
The active suppression of fibroblast proliferation leads to the
for this devastating condition that will help millions of
inhibition of collagen formation and deposition. As previously
patients worldwide.
explained, cannabinoids can actively suppress inflammation by
downregulating the pro-inflammatory cytokines such as IL-2,
IL-1β, TNF-α, IFN-γ, IL-12, IL-8, IL-6, IL-15 (Wang et al.,
2020). Due to this effect of cannabis, the fibrosis progression AUTHOR CONTRIBUTIONS
may stop. In comparison with drugs currently applied for
NP, OK, and IK contributed to the conceptualization and
treating pulmonary fibrosis, cannabinoids can also suppress the
design. NP and MZ contribute to the draft preparation.
MMP/TIMP, PPAR and other pathways involved in fibrogenesis
OK and IK contributed to the analysis, editing, and
(Table 5). We can conclude that cannabis affects the same
supervision. All authors were involved in a review preparation
pathways as other drugs currently used medicine in fibrosis
and editing.
treatment, but it has a little- documented negative effects on
patients as compared to other drugs used.
ACKNOWLEDGMENTS
CONCLUSION
The authors acknowledge the financial support of NSERC and
Fibrosis is a pathological process that may affect many organs. MITACS. The content of the manuscript has been included in
Significant improvement in understanding the tissue fibrosis NP’s Master’s thesis.
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published: 11 October 2021

The Potential Use of Cannabis in

Fibrosis is a condition characterized by thickening or/and scarring of various tissues.

TABLE 1 | Main types of fibrosis.

Organ/tissue Type of fibrosis References

Skin Hypertrophic scar Rabello et al. (2014)

Hemostasis 1-3 days

Intrinsic pathway Extrinsic pathway

Contact activation Injury

Prothrombinase complex, VIII, Platelets, Ca2+

TABLE 2 | Key mediators of inflammation and fibrogenesis.

Substance Production site Effects References

Inﬂammatory Clearance phase Ingrowth of granulaon ssue

FIGURE 3 | Phases of proliferation and granulation.

Pericytes Resident fibroblasts

Mesothelial cells ECM CD34+, CD45+

TABLE 3 | Single- and multi-component medications targeting fibrosis factors.

Group Target or Mechanism of action Drug name Disease Reference/trial

Single-component medications targeting extracellular factors

TABLE 4 | Anti-fibrotic effect of cannabinoids.

Compound The mechanism of action References

2-AG Generally considered as a fibrogenic agent, however, it is Tam et al. (2011)

Rimonabant The suppression of expression of fibrogenic mediators Giannone et al. (2012)

AM1241 The downregulation of expression of collagen I, collagen III, Li et al. (2016)

SLV319 The suppression of glucose transporter 2; reduction in Hinden et al. (2018)

JD5037 The suppression of glucose transporter 2; reduction in Hinden et al. (2018)

Lenabasum Stimulating PPAR-γ signaling Gonzalez et al. (2012)

improvement on mycophenolate that has an anti-fibrotic activity

Acvaon of platelets and formaon of ﬁbrin clot

A single-component medication: Cannabis

The mechanism of action of asingle-component medication vs. cannabis

• TGF-β inhibitor (Pirfenidone) • TGF-β inhibitor

The mechanism of action of a multi-component medication vs. cannabis

A multi-component medication: Cannabis

• TGF-pc/MMP-2c inhibitor (Fuzhenghuayu) • TGF-β1/Smad2 inhibitor

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