Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ

Abstract

Models of liver fibrosis, which include cell culture models, explanted and biopsied human material, and experimental animal models, have demonstrated that liver fibrosis is a highly dynamic example of solid organ wound healing. Recent work in human and animal models has shown that liver fibrosis is potentially reversible and, in specific circumstances, demonstrates resolution with a restoration of near normal architecture. This Review highlights the manner in which studies of models of liver fibrosis have contributed to the paradigm of dynamic wound healing in this solid organ.

Figure 1. Sinusoidal events in the development of liver fibrosis.

Injury to hepatocytes results in the recruitment and stimulation of inflammatory cells, as well as the stimulation of resident inflammatory cells (including Kupffer cells). Factors released by these inflammatory cells lead to transformation of HSCs into a myofibroblast-like phenotype. HSC activation leads to accumulation of scar (fibrillar) ECM. The presence of a fibrillar ECM in the Disse space has consequences for hepatocyte function, leading to the loss of microvilli and endothelial fenestrae. Therefore, the loss of normal tissue architecture contributes to impairment of organ function. Figure modified with permission from Journal of Biological Chemistry (119).

Figure 2. Repertoire of activities of the activated myofibroblast-like HSC.

Activated HSCs, which are myofibroblast-like in phenotype, demonstrate a plastic and metabolically active phenotype that is proliferative, fibrogenic, and contractile. HSCs also release mediators that regulate ECM degradation (MMPs and TIMPs), chemotaxis, and leukocyte chemoattraction. The shedding of retinoids might be a critical, though as yet poorly defined, signal regulating fibrogenesis. During resolution of liver injury, activated HSCs and myofibroblasts have been demonstrated to undergo apoptosis. It is also possible that spontaneous reversion to a more quiescent phenotype might occur. Figure modified with permission from Journal of Biological Chemistry (119).

Figure 3. Diagramatic representation of the possible sources of liver myofibroblasts.

There is considerable evidence supporting the notion that HSCs are a major source of myofibroblasts in the injured liver. Additionally, contributions to the myofibroblast population might come from portal myofibroblasts. Most recently, BM stem cells have been demonstrated to contribute to the inflammatory cell population and the myofibroblast population in the injured liver, which might occur directly or through an intermediary cell, such as a quiescent HSC or CD45⁺ fibrocyte. Research is currently underway to determine the role of EMT in the development of liver myofibroblasts.

Figure 4. Liver cirrhosis is an example of dynamic wound healing.

Damage to the normal liver (i) results in inflammation and activation of HSCs (ii; identified by immunohistochemistry, with staining for α-SMA [brown]) to secrete fibrillar collagens, culminating in the development of fibrosis (iii) and ultimately cirrhosis (iv). Withdrawal of the injurious agent can allow remodeling of the fibrillar matrix, leading to attenuated cirrhosis (v). Spontaneous resolution of fibrosis after removal of injury results in a return to near-normal architecture (vi). Whether complete resolution of cirrhosis can occur is currently unknown. Figure modified with permission from BMJ (3).