The PIM1 signaling pathway seems to be involved in idiopathic pulmonary fibrosis (IPF), according to a new study published in JCI Insight. This finding suggests that targeting this pathway could be a promising therapeutic approach to inhibit the progression of the disease.

Here, a team of researchers led by Giovanni Ligresti, PhD, conducted experiments in a mouse model of IPF to clarify the biological mechanisms causing persistent lung fibrosis in aging. IPF is associated with aging and characterized by progressive lung scarring. 

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The researchers performed RNA sequencing on lung fibroblasts obtained from young and aged mice with lung injury caused by bleomycin treatment, a common model for IPF. 

They found that the injured fibroblasts of aged animals at the peak of fibrosis were in a constant profibrotic state, and this was not the case in the injured fibroblasts of young animals. A profibrotic state is characterized by the increased expression of genes involved in inflammation, matrix remodeling, and cellular survival. The researchers identified PIM1 (proviral integration site for Moloney murine leukemia virus 1) and its target NFATc1 (nuclear factor of activated T cells-1) as transcription factors potentially involved in this persistent profibrotic state. 

The following findings supported their hypothesis:

  • PIM1 and NFATc1 transcripts were enriched and their corresponding proteins were abundant in a pathogenic fibroblast population in IPF lungs. 
  • The overexpression of PIM1 in normal human lung fibroblasts in vitro triggered their fibrogenic activation in an NFATc1-dependent manner. 
  • The inhibition of PIM1 dampened the activation of IPF fibroblasts and rendered them more sensitive to apoptotic stimuli.
  • Inhibiting PIM1 signaling in IPF lung tissue inhibited the expression of prosurvival genes as well as the secretion of collagen.

The researchers concluded that the PIM1 signaling pathway is “a key contributor of the persistent fibroblast activation observed in aged mice post-bleomycin.”

PIM1 is a proto-oncogene encoding a serine/threonine protein kinase. It is minimally expressed in healthy tissue and has previously been shown to be involved in the pathogenesis of lung disease.

Reference

Pham TX, Lee J, Guan J, et al. Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis. JCI Insight. Published online February 15, 2022. doi:10.1172/jci.insight.153672