Pulmonary fibrosis is a progressively aggravating lethal disease that is a serious public health concern. Although the incidence of this disease is increasing, there is a lack of effective therapies. In recent years, the pathogenesis of pulmonary fibrosis has become a research hotspot. p53 is a tumor suppressor gene with crucial roles in cell cycle, apoptosis, tumorigenesis, and malignant transformation. Previous studies on p53 have predominantly focused on its role in neoplastic disease. Following in-depth investigation, several studies have linked it to pulmonary fibrosis. This review covers the association between p53 and pulmonary fibrosis, with the aim of providing novel ideas to improve the clinical diagnosis, treatment, and prognosis of pulmonary fibrosis.
Background: Phenylalanine levels are associated with pulmonary hypertension in metabolic profiling clinical studies. However, the pathophysiologic role of phenylalanine on pulmonary circulation is still unclear. We experimentally addressed the direct impact of phenylalanine on pulmonary circulation in rats and explored the underlying molecular pathway. Methods and results: Phenylalanine was injected intraperitoneally into Sprague-Dawley rats (400 mg/100g body weight) as a single dose or daily in a chronic manner for 2, 3 and 4 weeks. Chronic injection of phenylalanine induced pulmonary hypertension with time-dependent severity evidenced by elevated pulmonary artery pressure and pulmonary vascular resistance, as well as pulmonary artery and right ventricular hypertrophy. Using tandem mass spectrometry analysis, we found a quick 2-fold increase in blood level of phenylalanine 2 hours following injection. This increase led to a significant accumulation of phenylalanine in lung after 4 hours which remained sustained at up to 3-fold increase after 4 weeks. In addition, cellular thermal shift assay with lung tissues from phenylalanine-injected rats reveals the binding of phenylalanine to the calcium-sensing receptor (CaSR). In vitro experiments with cultured pulmonary arterial smooth muscle cells showed that phenylalanine activated CaSR as indicated by the increase in intracellular calcium content, which was attenuated or diminished by the inhibition or knockdown of CaSR. Finally, the global knockout or lung-specific knockdown of CaSR significantly attenuated phenylalanine-induced pulmonary hypertension. Conclusions: Chronic phenylalanine injection induces pulmonary hypertension through binding to CaSR and its subsequent activation.
Our results suggest that glyceraldehyde-3-phosphate dehydrogenase plays a critical role in determining the superior functions of female bone marrow-derived mesenchymal stem cells in cell therapy against pulmonary arterial hypertension by regulating [Ca(2+)]i signal-associated cellular behaviours.
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