Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction

Abstract

Fibrosis is an inadequate response to tissue stress with very few therapeutic options to prevent its progression to organ dysfunction. There is an urgent need to identify drugs with a therapeutic potential for fibrosis, either by designing and developing new compounds or by repurposing drugs already in clinical use which were developed for other indications. In this Perspective, we summarize some pathways and biological targets involved in fibrosis development and maintenance, focusing on common mechanisms between organs and diseases. We review the therapeutic agents under experimental development, clinical trials, or in clinical use for the treatment of fibrotic disorders, evaluating the reasons for the discrepancies observed between preclinical and clinical results. We also discuss the improvement that we envision in the development of therapeutic molecules able to achieve improved potential for treatment, including indirect modulators, targeting approaches, or drug combinations.

Purine adducts as a presumable missing link for aristolochic acid nephropathy‐related cellular energy crisis, potential anti‐fibrotic prevention and treatment

“…Although it is a continuous process, fibrosis has been divided into four phases (namely priming, activation, execution and progression) simply for clarity (Liu, 2011). There are various approaches to combat fibrosis, hence many great articles have emerged in recent years compiling information on fibrosis therapy (Allinovi et al, 2018; Breyer & Susztak, 2016; Györfi et al, 2018; Juillerat‐Jeanneret et al, 2018; Nanthakumar et al, 2015). A review of the available literature is beyond the scope of this article since it has already been done by others.…”

Regulation of Fibroblast Activation Protein-α Expression: Focus on Intracellular Protein Interactions

“…In response to tissue stress and injury, like local inflammation, wound healing, cancer, or after organ transplantation, repair mechanisms may result in two distinct phenomena: a normal regenerative process involving transient fibrosis, limited in time, in which injured tissues and cells are replaced by cells of the normal phenotype to maintain tissue homeostasis, or a pathological chronic uncontrolled fibrosis in which activated (myo)­fibroblasts and inflammatory cells permanently replace normal tissue. A key point in the development of both regenerative or pathological fibrosis is the presence of activated (myo)­fibroblasts . In comparison with their resting counterparts, activated (myo)­fibroblasts secrete proline-rich extracellular matrix (ECM) proteins and collagens.…”

“…The role of FAP-α in promoting diseases such as fibrosis and cancer is generally accepted. − FAP-α is upregulated at the mRNA and protein levels in the stroma of tumors, such as colon cancer, and its expression is associated with advanced stages and aggressive disease progression. − In fibroblasts induction of FAP-α has been associated with transforming growth factor (TGF-β) signaling and inflammatory pathways . Down-regulation of FAP-α leads to a more epithelial phenotype and inhibits the progression of colon cancer, an effect rescued by TGF-β, whereas gain of FAP-α induces a more contractile cell phenotype.…”

Recent Advances in Fluorescence Imaging of Pulmonary Fibrosis in Animal Models

“…In particular, PF is considered a risk factor for the severe evolution of coronavirus disease 2019, which is rapidly spreading and escalating into a global pandemic affecting the health of billions of people ( Crisan-Dabija et al, 2020 ; George et al, 2020 ). Given that lung transplantation is the only effective treatment for PF to date ( Juillerat-Jeanneret et al, 2018 ), the early diagnosis of PF is critical to help reduce patient morbidity and improve patient survival.…”