Abstract
Fibrotic disease, which is implicated in almost half of all deaths worldwide, is the result of an uncontrolled wound healing response to injury in which tissue is replaced by deposition of excess extracellular matrix, leading to fibrosis and loss of organ function. A plethora of genome-wide association studies, microarrays, exome sequencing studies, DNA methylation arrays, next-generation sequencing, and profiling of noncoding RNAs have been performed in patient-derived fibrotic tissue, with the shared goal of utilizing genomics to identify the transcriptional networks and biological pathways underlying the development of fibrotic diseases. In this review, we discuss fibrosing disorders of the skin, liver, kidney, lung, and heart, systematically (1) characterizing the initial acute injury that drives unresolved inflammation, (2) identifying genomic studies that have defined the pathologic gene changes leading to excess matrix deposition and fibrogenesis, and (3) summarizing therapies targeting pro-fibrotic genes and networks identified in the genomic studies. Ultimately, successful bench-to-bedside translation of observations from genomic studies will result in the development of novel anti-fibrotic therapeutics that improve functional quality of life for patients and decrease mortality from fibrotic diseases.
Highlights
While fetal skin is capable of scarless regeneration [14], postnatal skin injury results the formation of a scar, and a sustained remodeling response leads to deposition of excess extracellular matrix (ECM) and fibrotic scarring with loss of structure and function [6]
In venous leg ulcers (VLU) in particular, the wound bed is histopathologically characterized by disorganized ECM, marked fibrosis, and chronic inflammatory infiltrates, all of which contribute to impaired healing; increased presence of dense fibrosis and high mature collagen levels in VLUs correlate with poor healing outcomes in the clinical setting [74]
Beyond chronic kidney disease (CKD), renal fibrosis often occurs in the setting of systemic lupus erythematosus (SLE) as a consequence of autoimmune inflammation leading to lupus nephritis
Summary
Fibrotic disorders are implicated in nearly 45% of all deaths in the developed world [1]. We summarize genomic studies designed elucidate the injury-driven pathogenesis of human fibrosing disorders of the skin, liver, kidney, lung, and heart These encompass genome-wide association studies (GWAS) identifying loci that confer susceptibility to fibrotic disease; transcriptome analyses (microarray, whole exome and RNA-sequencing) identifying differential gene expression changes in lesional fibrotic tissue and ex vivo fibroblasts; profiling of epigenomic factors, non-coding RNA (microRNA (miRNA), circular RNA (circRNA), and long non-coding RNA (lncRNA)); and DNA methylation studies that define global regulatory networks of fibrosis. Neutrophils release neutrophil extracellular traps (NETs) that further activate fibroblasts and promote differentiation into myofibroblasts [11] Dysregulation of these processes in any connective tissue-containing organ can cause excessive ECM deposition and tissue fibrosis, leading to loss of organ function [6]. Robust yet short-lived wound healing response of injured oral epithelium can result in scarless healing [12], while a prolonged response with pro-fibrotic mediators can produce the non-healing bed of chronic wounds [8,13]
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