E1A-binding protein p300 (p300) plays a key role in the development of lung fibrosis in alveolar type II (ATII) cells, which has significant consequences for the diagnosis and treatment of patients with idiopathic pulmonary fibrosis (IPF).
These findings come from a study conducted in human lung samples collected from the tissue bank of the Severance Hospital in Seoul, South Korea, and published in the journal Experimental & Molecular Medicine.
IPF is a chronic, progressive, fatal interstitial lung disease of unknown origin, with no clear approach for effective treatment. Although extensive investigations have been conducted to elucidate the underlying mechanisms responsible for the development of IPF, the cause of the disease remains unknown.
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The antifibrotic medications nintedanib and pirfenidone have been approved as treatments for patients with the disorder, but their effectiveness appears to be limited. The development of new therapies designed to overcome the limitations of current treatments for IPF thus remains critical.
Read more about experimental therapies for patients with IPF
In the current study, tissue from patients with IPF and control samples from the normal lungs of patients with lung cancer were obtained. Conditional lung epithelial cell-specific p300 knockout mice were used to confirm the ATII cell-specific function of p300 and the underlying mechanism linked to the progression of pulmonary fibrosis in vivo.
Based on study results, immunohistochemistry demonstrated that the lung samples of patients with IPF displayed significantly increased levels of p300 compared with the lung control samples. Recognizing that honeycombing is a key criterion in the diagnosis of IPF, exhibiting a characteristic appearance of variably sized cysts, the researchers evaluated the expression of p300 in honeycomb cysts in IPF lung samples and normal airway regions from the control samples with the use of p300 immunohistochemistry.
They found elevated levels of p300 in the honeycomb cysts of the lungs from the IPF samples compared with the samples from the control lungs. In the IPF lung samples, the expression of p300 was vastly increased in the bronchial and alveolar epithelium. Of note, levels of histone acetyltransferase proteins other than p300 were not elevated in patients with IPF compared with the controls.
Further, the ubiquitin C-terminal hydrolase L3-mediated deubiquitinase of p300 was associated with transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 via the cooperative activity of p300 and CCAAT/enhancer-binding protein (C/EBP) family, which includes C/EBPα and C/EBPβ, thus generating M2 macrophage polarization. The selective blockade of p300 activity in ATII subsequently led to the reprogramming of M2 macrophages into antifibrotic macrophages.
According to the researchers, “Collectively, our findings demonstrate the functional significance of p300 in pulmonary fibrosis and suggest that p300 could serve as a novel therapeutic target for IPF therapy.” They concluded that “We provided a basis for the future development of a novel IPF therapy based on the inhibition of p300 activity or stability.”
Reference
Lee SY, Park S-Y, Lee S-H, et al. The deubiquitinase UCHL3 mediates p300-dependent chemokine signaling in alveolar type II cells to promote pulmonary fibrosis. Exp Mol Med. Published online August 1, 2023. doi:10.1038/s12276-023-01066-1
