The novel peptide DR4penA attenuates the bleomycin‐ and paraquat‐induced pulmonary fibrosis by suppressing the TGF‐β/Smad signaling pathway

Abstract

Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR‐NH2), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure–activity relationship and rational design, we introduced an unnatural hydrophobic amino acid (α‐(4‐pentenyl)‐Ala) into DR8 and screened the novel peptide DR4penA (DHNα‐(4‐pentenyl)‐APQIR‐NH2), which had higher anti‐PF activity, higher antioxidant activity and a longer half‐life than DR8. Notably, DR4penA attenuated bleomycin‐ and paraquat‐induced PF, and the anti‐PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF‐β/Smad pathway in TGF‐β1‐induced A549 cells and paraquat‐induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.

Early diagnosis and staging of paraquat-induced pulmonary fibrosis using [18F]F-FAPI-42 PET/CT imaging

“…[ 68 Ga]Ga-FAPI-46 has demonstrated efficacy in assessing bleomycin-induced idiopathic pulmonary fibrosis by targeting highly expressed FAP cells, showing promising applications [ 8 ]. Bleomycin induces cellular necrosis and apoptosis, inflammation, and fibrosis via DNA strand breakage, free radical generation, oxidation of fatty acids, and destabilization of membranes [ 18 , 27 ]. Pulmonary fibrosis induced by bleomycin is typically self-limiting, with potential rapid recovery and partial return to normalcy [ 20 ].…”

“…Utilizing a biochemical cyclotron accelerator liquid target (Cyclone 18/9, IBA), high-pressure [ 18 O]H 2 O (purity exceeding 99.7%) was irradiated with 18 MeV protons to generate carrier-free [ 18 F]fluoride. The resulting 18 F crude solution was passed through an activated QMA column, rinsed with 10 mL of sterile water for injection, dried with nitrogen (N 2 ), and subsequently eluted with 0.35 mL of 0.5 mol/L sodium acetate solution. 0.2 mg of FAPI-42 was dissolved in 300 µL of dimethyl sulfoxide (DMSO), followed by the addition of 60 µL of aluminum chloride (AlCl 3 , 2 mmol/L).…”

“…0.2 mg of FAPI-42 was dissolved in 300 µL of dimethyl sulfoxide (DMSO), followed by the addition of 60 µL of aluminum chloride (AlCl 3 , 2 mmol/L). This mixture was then combined with the eluate containing 18 F and allowed to react at 105 °C for 15 min. Following this, 3.5 mL of sterile water for injection was introduced into the reaction vial, mixed with N 2 , and the resulting product was passed through an activated HLB column, followed by a wash with 30 mL of sterile water for injection.…”

“…However, the pulmonary fibrosis induced by PQ differs from the traditional bleomycin-induced fibrosis. Bleomycin primarily activates extracellular matrix remodeling and collagen degradation pathways, leading to rapid and often self-limiting fibrotic progression [18][19][20]. In contrast, PQ initially triggers cell cycle regulation processes upon lung entry, progressing to fatal delayed progressive pulmonary fibrosis [21].…”

“…Further research is therefore warranted to investigate the potential of FAPI PET imaging for early detection of PQ-induced pulmonary fibrosis. Furthermore, the lower positron yield ( 68 Ga, 89.14% vs. 18 F, 96.86%) and higher positron energy ( 68 Ga, 1,899 keV vs. 18 F, 633 keV) of 68 Ga as well as the inferior image spatial resolution of 68 Ga compared to 18 F (2.4 mm vs. 1.4 mm in all directions) may impact image quality and diminish diagnostic accuracy, particularly for pulmonary fibrosis, which shows diffuse symptoms in lung tissue, distinguishing it from concentrated tumors [22]. Furthermore, 18 F, with its routine cyclotron production and biologically suitable half-life of 110 min, stands out as a preferred radiotracer for PET imaging studies [23].…”