1. Introduction
Fibrotic diseases with high morbidity and mortality all over the world
(Klinkhammer, Floege and Boor 2018, Henderson, Rieder and Wynn 2020) are
characterized by excessive deposition of extracellular matrix (ECM)
(Distler et al. 2019). It can potentially affect all organs and tissues
in the body including multisystem diseases such as systemic sclerosis as
well as individual organs containing pulmonary, kidney, hepatic, cardiac
and bladder fibrosis(shown in Fig 1) (Rosenbloom, Ren and Macarak
2016). At present, there are few effective drugs for the direct
treatment of fibrosis in clinic. A large number of diseases related to
fibrosis urgently need specific drugs to improve the survival status of
patients.
Fibrosis is the common outcome of tissue repair response which tends to
be dysregulated following kinds of trigger and tissue injury, most
significantly during chronic inflammatory diseases (Henderson et al.
2020). The excessive accumulation of ECM components including collagen
and fibronectin, is a common and significant stage of tissue repair
process in all organs. When tissues are damaged, local tissue
fibroblasts tend to activate and occurred a series of changes including
enhance their contractility, secrete inflammatory mediators, and
excessive generated of ECM components, which sponsor the wound-healing
response. When the injury reduced or vanished, the wound-healing
response tend to be effective, exhibiting in only a short-lived enhance
of the accumulation of ECM components and promoting the renewal of
functional tissue structure. In contrast, when the injury persistent
existence, the wound-healing response transformed into
microenvironmental changes including ECM generating cells raise in
amount or become immoderately active, which eventually leads to the
formation of substantial scar formation and injury of normal organ
structure (Pakshir and Hinz 2018).
In the different organs, a good deal of clinical research and animal
experiments’ evidence has obviously built the strong connection of cell
death with fibrosis (Weiskirchen, Weiskirchen and Tacke 2019). Over the
last decade, it has become definite that there are many forms of cell
death, and diverse forms of cell death can be triggered in diseases,
initiating different replies and biological results (Sauler, Bazan and
Lee 2019). Regulated cell death (RCD) is a primary approach for human
body to cleanup injured, infected, or surplus cells. In the past,
apoptosis was considered the unique form of RCD. However, recent studies
have discovered several new modes of RCD including necroptosis,
pyrolysis,
ferroptosis and autophagic cell death (Stockwell et al. 2017, Vande
Walle and Lamkanfi 2016, Choi et al. 2019, Tang et al. 2020). With the
in-depth understanding of the RCD mechanism, more and more evidence
indicated that these RCD mechanisms are closely related to organ
fibrosis (Shojaie, Iorga and Dara 2020, Schwabe and Luedde 2018). By
straightly obstructing the mediators that regulate each mode of RCD or
promote the mediators that response to certain types of RCD may bring us
new opportunities to treat fibrotic diseases. The latest research shows
that apoptosis and necroptosis emerge higher research value in the
process of fibrosis, compared with pyrolysis, ferroptosis and
autophagy(Schwabe and Luedde 2018). In addition, compared with
apoptosis, necroptosis can cause cellular contents to flow out, further
trigger a large amount of inflammation, accelerate the process of
fibrosis, and may lead to the irreversibility of fibrosis. Therefore,
the aim of this review is to summarize our understanding of the
necroptosis in organ fibrosis, so as to provide certain research ideas
for the therapy of organ fibrosis or the development of new drugs.