Nintedanib (NDN), a tyrosine kinase inhibitor, has been shown to have anti-tumor, anti-inflammatory, and anti-fibrotic effects in several reports. We investigated the protective effects of NDN against polyhexamethylene guanidine phosphate (PHMG)-induced lung fibrosis in mice. The following three experimental groups were evaluated: (1) vehicle control; (2) PHMG (1.1 mg/kg); and (3) PHMG & NDN (60 mg/kg). PHMG induced pulmonary inflammation and fibrosis by intratracheal instillation in mice. In contrast, NDN treatment effectively alleviated the PHMG induced lung injury, and attenuated the number of total cells and inflammatory cells in the bronchoalveolar lavage fluid, including the fibrotic histopathological changes, and also reduced the hydroxyproline content. NDN also significantly decreased the expression of inflammatory cytokines and fibrotic factors, and the activation of the NLRP3 inflammasome in lung tissues. These results suggest that NDN may mitigate the inflammatory response and development of pulmonary fibrosis in the lungs of mice treated with PHMG.

Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MT^GFP). When MT^GFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MT^GFP injected intravenously into normal mice, MT^GFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.

(1) Background: Progression of chronic obstructive pulmonary disease (COPD) leads to irreversible lung damage and inflammatory responses; however, biomarker discovery for monitoring of COPD progression remains challenging. (2) Methods: This study evaluated the metabolic mechanisms and potential biomarkers of COPD through the integrated analysis and receiver operating characteristic (ROC) analysis of metabolic changes in lung, plasma, and urine, and changes in morphological characteristics and pulmonary function in a model of PPE/LPS-induced COPD exacerbation. (3) Results: Metabolic changes in the lungs were evaluated as metabolic reprogramming to counteract the changes caused by the onset of COPD. In plasma, several combinations of phenylalanine, 3-methylhistidine, and polyunsaturated fatty acids have been proposed as potential biomarkers; the α-aminobutyric acid/histidine ratio has also been reported, which is a novel candidate biomarker for COPD. In urine, a combination of succinic acid, isocitric acid, and pyruvic acid has been proposed as a potential biomarker. (4) Conclusions: This study proposed potential biomarkers in plasma and urine that reflect altered lung metabolism in COPD, concurrently with the evaluation of the COPD exacerbation model induced by PPE plus LPS administration. Therefore, understanding these integrative mechanisms provides new insights into the diagnosis, treatment, and severity assessment of COPD.

The mitochondria are essential organelles not only providing cellular energy in the form of ATP, but also regulating the inflammatory response and the cell death program. Mitochondrial dysfunction has been associated with various human diseases, including metabolic syndromes as well as inflammatory and neurodegenerative diseases. Acute respiratory distress syndrome (ARDS) is an acute pulmonary disorder characterized by uncontrolled alveolar inflammation, apoptotic lung epithelial/endothelial cells, and pulmonary edema. Despite the high mortality of ARDS, an effective pharmacotherapy to treat this disease has not been established yet. Therefore, identifying a novel targeted therapy for ARDS is important. Recently, exogenous mitochondrial transplantation was reported to be beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transplantation on ARDS in vitro and in vivo. Mitochondria were isolated from human stem cells. For in vitro efficacy of mitochondrial transplantation on the inflammation and cell death, murine alveolar macrophages MH-S and human pulmonary microvascular endothelial cells HPMECs were exposed to LPS, respectively. The ARDS mice model established by a single intratracheal instillation of LPS was used for in vivo efficacy of intravenously treated mitochondria. Our results showed that the mitochondria isolated from human stem cells exhibited an anti-inflammatory effect against alveolar macrophages and an anti-apoptotic effect against the alveolar epithelial cells. Furthermore, intravenous mitochondrial treatment was associated with the attenuation of lung injury in the LPS-induced ARDS mice. Dual effects of mitochondria on anti-inflammation and anti-apoptosis support the potential of mitochondrial transplantation as a novel therapeutic strategy for ARDS.