Page 27 - GPD-3-3

Gene & Protein in Disease Modulating immune response in liver by curcumin

as a versatile protein responsible for the transport and in two stages. The initial stage encompasses early alterations
storage of copper in the body. In addition, it acts as in gene expression that occur shortly after the injury. The
an antioxidant by scavenging reactive oxygen species subsequent phase, known as perpetuation, entails the
(ROS) and inhibiting their production. Research has maintenance of the activated phenotype, leading to the
shown that the administration of curcumin leads to a progression of fibrosis. During this process, activated
notable reduction in the levels of NO, serum amyloid A, HSCs lose their star-like shape and lipid droplets and start
haptoglobin, and ceruloplasmin induced during an APR to producing excessive amounts of ECM components such
aflatoxin exposure. These findings suggest that curcumin as collagens (types I, III, and IV), fibronectin, laminin,
offers protective effects against hepatotoxicity and has proteoglycans, and pro-inflammatory mediators. The
the potential to regulate liver homeostasis by modulating activation and recruitment of various cellular effectors,
APRs. such as endothelial cells, KCs, infiltrating immune cells,
and platelets, are also initiated by the production of
3.3. Induction of chronic inflammation and fibrosis chemotactic and inflammatory substances. These cellular
The initiation of all liver diseases begins with the death effectors play a significant role in creating a pro-fibrogenic
of hepatocytes. When hepatocytes die or are injured, environment and sustaining HSC activation. Two major
they release intracellular substances known as DAMPs, cytokines, TGF-β and platelet-derived growth factor, play
which signal neighboring cells such as HSCs and KCs. significant roles in HSC activation and proliferation. The
This process significantly contributes to the progression initiation phase is activated through paracrine stimulation
of fibrosis and inflammation. DAMPs consist of adenosine of HSCs by signals derived from KC and endothelial cells,
triphosphate (ATP), intracellular proteins, nucleic acids, along with products released from injured hepatocytes.
and high-mobility group box-1 (HMGB1). Necrotic In addition, exposure to ROS and lipid peroxides plays a
40
hepatocytes passively release DAMPs on account of the significant role in the initiation phase. 43,44 The perpetuation
disruption of their plasma membrane. In the context phase is a result of the continuous effects of these stimuli,
of liver diseases, HMGB1 is a well-studied DAMP. promoting the synthesis of proliferative, contractile,
Eukaryotic cells widely express this DNA-binding, non- inflammatory, and chemical-adjuvant mediators, as
histone nuclear protein, and necrotic hepatocytes release well as fibrogenesis and matrix degradation. Ultimately,
HMGB1 as a danger signal. On the other hand, apoptosis these signals contribute to the development of fibrosis
41
results in lower levels of these signals because the cellular (Figure 2). Enzymes involved in matrix component
components are mostly contained within apoptotic bodies. degradation, such as matrix metalloproteinases (MMPs),
However, hepatocyte apoptosis can still trigger a pro- play a role in replacing normal ECM with a modified
fibrogenic response through Fas death receptor activation. matrix. ECM remodeling encompasses alterations in
In addition, apoptotic bodies released by hepatocyte stiffness, flexibility, and density, which are associated
apoptosis can be engulfed by HSCs and KCs, leading to with disruptions in the production of its components. 45-48
responses involved in the pathogenesis of fibroproliferative Furthermore, activated cells exhibit elevated expression
processes. Furthermore, the DNA components present of tissue inhibitors of metalloproteinase 1 (TIMP-1) and
within the apoptotic bodies of damaged hepatocytes alpha-smooth muscle actin (α-SMA), which contribute
activate TLR9 signaling on the surface of HSCs, thereby to the transition from an adipocytic phenotype to a pro-
promoting the production of collagen. 42 fibrogenic and inflammatory phenotype. Physiologically,
44
This process is initiated by the release of DAMPs, myofibroblasts play a crucial role in repairing damaged
which triggers KC activation and the recruitment of tissue. After short-term injury, these cells are efficiently
monocyte-derived macrophages, ultimately resulting eliminated through apoptosis or inactivation. However, in
in ROS production. HSCs, the primary progenitor cells cases of chronic injury, the continuous activation of HSCs
for myofibroblasts, play a crucial role in the responses disrupts the delicate balance between ECM deposition and
leading to collagen synthesis and extensive deposition dissolution, leading to liver fibrosis progression. As fibrosis
of extracellular matrix (ECM) components. In a healthy advances, the increase in the activated HSC population
liver, HSCs are quiescent and non-proliferative, located and the contractility of myofibroblasts contribute to the
around the sinusoids with a star-like shape and numerous constriction of hepatic sinusoids. This constriction impairs
lipid droplets dispersed in their cytoplasm. However, blood flow and nutrient exchange, ultimately contributing
when the liver is injured, HSCs undergo activation and to liver dysfunction. During the initial stage of injury, pro-
transformation from a quiescent state to a myofibroblast inflammatory macrophage populations play a dominant
phenotype, which is characterized by extensive role. The immediate response of KCs to the ensuing
proliferation and contractility. This transformation occurs stimulus is to secrete IL-1β, TNF-α, C–C motif chemokine

Volume 3 Issue 3 (2024) 7 doi: 10.36922/gpd.3186