JoVE - Journal of Visualized Experiments
JoVE Visualize
Contact Us

p53-miR-34a Feedback in Lung Fibroblasts Regulates Antifibrotic Effects of CSP7, Nintedanib and Pirfenidone

  • 0Texas Lung Injury Institute, Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708.
American Journal of Physiology. Lung Cellular and Molecular Physiology +

|

August 18, 2025

|

August 18, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Idiopathic pulmonary fibrosis (IPF) treatments involving CSP7, Nintedanib, and Pirfenidone rely on the p53-microRNA-34a pathway. Restoring this pathway in lung fibroblasts is crucial for anti-fibrotic effects in IPF.

Area Of Science

  • Pulmonary Medicine
  • Fibrosis Research
  • Molecular Biology

Background

  • Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with progressive lung function loss.
  • Lung fibroblasts are key effector cells in IPF pathogenesis.
  • The p53-microRNA-34a feedback loop is implicated in the anti-fibrotic effects of CSP7.

Purpose Of The Study

  • To investigate the role of the p53-microRNA-34a pathway in the anti-fibrotic effects of Nintedanib and Pirfenidone.
  • To compare the efficacy of CSP7, Nintedanib, and Pirfenidone in a bleomycin-induced pulmonary fibrosis (PF) mouse model.
  • To evaluate the impact of targeted deletion of p53 or microRNA-34a in lung fibroblasts on PF development and treatment response.

Main Methods

  • Utilized wild-type, p53 flox, and microRNA-34a flox mice, along with tamoxifen-inducible conditional knockout mice (p53<sup>cKO</sup>, miR-34a<sup>cKO</sup>) lacking these genes in lung fibroblasts.
  • Induced pulmonary fibrosis using bleomycin.
  • Administered CSP7 (intraperitoneal or inhaled), Nintedanib, or Pirfenidone to mice and assessed outcomes including body weight, lung function, survival, and extracellular matrix deposition.

Main Results

  • p53<sup>cKO</sup> and miR-34a<sup>cKO</sup> mice showed exacerbated PF phenotypes, including greater lung function loss, reduced survival, and increased extracellular matrix deposition compared to control mice.
  • Treatment with CSP7, Nintedanib, or Pirfenidone improved survival, body weight, and lung function in wild-type mice.
  • Combination therapy of CSP7 with Nintedanib or Pirfenidone was more effective than monotherapy.
  • PF mice with genetic deletion of p53 or microRNA-34a in fibroblasts were resistant to these anti-fibrotic treatments.

Conclusions

  • The p53-microRNA-34a feedback induction in lung fibroblasts is essential for the anti-fibrotic efficacy of CSP7, Nintedanib, and Pirfenidone.
  • Targeting the p53-microRNA-34a pathway holds therapeutic potential for IPF.
  • Further research into combination therapies modulating this pathway may offer improved treatment strategies for IPF.

Keywords:

Related Concept Videos

Abnormal Proliferation 02:23

4.6K

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...

Negative Regulator Molecules 01:23

35.9K

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.

Three of the best-understood negative regulators are p53, p21, and retinoblastoma protein (Rb). The regulatory roles of each of these proteins were discovered after faulty copies were found in cells with uncontrolled replication (i.e.,...

Interactions Between Signaling Pathways 01:19

6.4K

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...