Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jun 3;22(11):6041.
doi: 10.3390/ijms22116041.

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

Yoshitoshi Kasuya  1   2 , Jun-Dal Kim  3 , Masahiko Hatano  1 , Koichiro Tatsumi  4 , Shuichi Matsuda  1   4
Affiliations
Review

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

Yoshitoshi Kasuya et al. Int J Mol Sci. .

Abstract

Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.

Keywords: c-Jun NH2-terminal kinase; idiopathic pulmonary fibrosis; p38 MAPK; stress-activated protein kinases.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic simplified representation of the JNK and p38 MAPK pathways in mammals. Both signaling pathways can be induced by inflammatory cytokines and profibrotic growth factors through an upstream activator sequence: MAP3K, MAP2K, and MAPK, promoting various regulatory proteins (kinases, transcription factors, transcriptional coregulators, post-transcriptional factors, and apoptosis-related factors) that are involved in the inflammatory and fibrotic responses.
Figure 2
Figure 2
The molecular mechanism of JNK-mediated pulmonary fibrosis. JNK participates in various cellular responses to profibrotic stimuli: apoptosis, necroptosis, and EMT of alveolar epithelial cells (AEC); FMD of fibroblasts; and maintenance of the myofibroblastic phenotype.
Figure 3
Figure 3
The molecular mechanism of p38-mediated pulmonary fibrosis. p38 participates in various cellular responses to profibrotic stimuli: EMT and cell injury of small airway epithelial cell (SAEC), invasion capacity and PG deposition of a myofibroblast, and M2 polarization and FMD promotion of a macrophage. Loss of DUSP10 leading to p38 activation seems to mediate the antifibrotic cellular functions. A more detailed evaluation regarding this point remains to be elucidated.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Nikolic I., Leiva M., Sabio G. The role of stress kinases in metabolic disease. Nat. Rev. Endocrinol. 2020;16:697–716. doi: 10.1038/s41574-020-00418-5. - DOI - PubMed
    1. Yue J., Lôpez J.M. Understanding MAPK signaling pathways in apoptosis. Int. J. Mol. Sci. 2020;21:2346. doi: 10.3390/ijms21072346. - DOI - PMC - PubMed
    1. Rehfeldt S.C.H., Majolo F., Goettert M.I., Laufer S. c-Jun N-terminal kinase inhibitors as potential leads for new therapeutics for Alzheimer’s diseases. Int. J. Mol. Sci. 2020;21:9677. doi: 10.3390/ijms21249677. - DOI - PMC - PubMed
    1. Zeke A., Misheva M., Reményi A., Bogoyevitch M.A. JNK signaling: Regulation and functions based on complex protein-protein partnerships. Microbiol. Mol. Biol. Rev. 2016;80:793–835. doi: 10.1128/MMBR.00043-14. - DOI - PMC - PubMed
    1. Jiang Y., Chen C., Li Z., Guo W., Gegner J.A., Lin S., Han J. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38δ. J. Biol. Chem. 1997;272:30122–30128. doi: 10.1074/jbc.272.48.30122. - DOI - PubMed

MeSH terms

Substances