Fibrosis usually results from dysregulated wound repair and is characterized by excessive scar tissue. It is a complex process with unclear mechanisms. Accumulating evidence indicates that epigenetic alterations, including histone acetylation, play a pivotal role in this process. Histone acetylation is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are enzymes that remove the acetyl groups from both histone and nonhistone proteins. Aberrant HDAC activities are observed in fibrotic diseases, including cardiac and pulmonary fibrosis. HDAC inhibitors (HDACIs) are molecules that block HDAC functions. HDACIs have been studied extensively in a variety of tumors. Currently, there are four HDACIs approved by the US Food and Drug Administration for cancer treatment yet none for fibrotic diseases. Emerging evidence from in vitro and in vivo preclinical studies has presented beneficial effects of HDACIs in preventing or reversing fibrogenesis. In this review, we summarize the latest findings of the roles of HDACs in the pathogenesis of cardiac and pulmonary fibrosis and highlight the potential applications of HDACIs in these two fibrotic diseases.

Objective: Ultraviolet B (UVB) is an important trigger of skin inflammation and lupus with leukocyte recruitment to inflamed skin. We recently reported the involvement of neutrophil NETosis in UVB-induced skin inflammation, and that NETotic nuclear envelope rupture is driven by PKCα-mediated nuclear lamin B disassembly. To address the role of Actin cytoskeleton in NETosis, we investigated the effects of Rho kinase (ROCK) and its downstream actomyosin cytoskeletal networks on PKCα nuclear translocation and NET formation, as well as their involvement in UVB-induced skin inflammation. Methods: We studied the dynamic changes of ROCK and actomyosin cytoskeletal networks during NETosis induction and their involvement in PKCα nuclear translocation. Using mice with hematopoietic-specific ROCK1 deficiency, we investigated the effects of ROCK1 deficiency on NETosis, and its involvement in UVB-induced skin inflammation. Results: Our time course studies demonstrated the dynamic changes of actin polymerization and ROCK activation, support the role of actin cytoskeleton in nuclear translocation of cytosolic PKCα in early stage of NETosis induction. Inhibition of actin polymerization or key molecules of the ROCK/MLCK/myosin pathway decreased PKCα nuclear translocation and NET formation. Genetic deficiency of ROCK1, inhibited NETosis ex vivo and in vivo , decreased extracellular display of NET-associated IL-17A, TNFα, IFNγ, and IFNα in inflamed skin, which were correlated with the ameliorated skin inflammation in UVB-irradiated mice with hematopoietic-specific ROCK1 deficiency. Conclusions: ROCK regulated NETosis through modulation of PKCα nuclear translocation via actomyosin cytoskeletal networks in neutrophils. ROCK1 deficiency ameliorated UVB-induced skin inflammation by attenuation of NETosis and NET-associated cytokines.