Mefunidone ameliorates lipopolysaccharide-induced acute lung injury through inhibiting MAPK signaling pathway and enhancing Nrf2 pathway.

BACKGROUND AND OBJECTIVE: Acute lung injury (ALI) is a life-threatening disease which has high mortality and lacks effective pharmacological treatments. Excessive inflammation and oxidative stress are the key pathogenesis of ALI. Mefunidone (MFD), a novel small molecule compound, displayed anti-inflammation and anti-oxidative stress effects on streptozocin (STZ) and db/db mice in our previous studies. In this study, we aimed to investigate the effects of MFD on lipopolysaccharide (LPS)-induced ALI and explore the potential molecular mechanisms. METHODS: We investigated the effects of MFD on LPS-induced ALI mouse model and LPS-stimulated immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: MFD could alleviate pulmonary structure disorder and attenuate pulmonary neutrophils infiltration induced by LPS. MFD could also decreased proinflammatory cytokines release and reduce reactive oxygen species (ROS) generation stimulated by LPS. Further, MFD could significantly reduce LPS-induced phosphorylation levels of mitogen-activated protein kinase (MAPK), increase expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and restore the expressions of antioxidant enzymes. CONCLUSION: Our results firstly supported that MFD effectively protected LPS-induced ALI against inflammation and oxidative stress through inhibiting MAPK signaling pathway and activating Nrf2 pathway.

Broncholithiasis: Treatment Evaluation in 63 Patients.

BACKGROUND: Broncholithiasis is a rare disease defined as the presence of calcified material (broncholith) within the tracheobronchial tree. We described our experience in broncholithiasis to provide a more effective clinical basis for the management of this condition. METHODS: We retrospectively reviewed the clinical characteristics, treatments, and outcomes of patients with broncholithiasis at Xiangya Hospital in China from May 2009 to November 2019. RESULTS: Sixty-three patients were enrolled in this study with a median age of 57 years. Cough (57.1%) was the most common symptom of broncholithiasis, followed by hemoptysis (23.8%). Tuberculosis was the most common comorbidity (38%), while 21 patients (30.0%) did not exhibit underlying diseases. Broncholiths within the bronchus led to airway dilation (19.0%), obstructive atelectasis (46.0%), and pneumonia (30.2%). The condition of most patients improved after undergoing endoscopic removal (76.5%) of the broncholiths. The condition of three patients (100%) improved after the surgical removal of the broncholiths. Of the 38 patients (60.3%) who failed to receive removal of broncholiths, 16 received anti-infection treatment, and the other 22 received observation. Most patients (50.0%) who were treated with anti-infectives showed an improvement, whereas the condition of 33.3% of patients who did not receive treatment worsened. CONCLUSIONS: Broncholithiasis is a benign bronchial disease that can cause complications. Endoscopic removal of broncholiths is considered as initial therapy and surgical removal is suggested as a second-line treatment. Treatment with anti-infectives is required for patients who fail to receive removal of broncholiths.

Caveolin-1 negatively regulates inflammation and fibrosis in silicosis.

Inhalation of crystalline silica causes silicosis, the most common and serious occupational disease, which is characterized by progressive lung inflammation and fibrosis. Recent studies revealed the anti-inflammatory and anti-fibrosis role of Caveolin-1 (Cav-1) in lung, but this role in silicosis has not been investigated. Thus, this study evaluated Cav-1 regulatory effects in silicosis. It was found that Cav-1 levels were significantly reduced in the lung from silicosis patients and silicotic mice. The silicosis models were established in C57BL/6 (wild-type) and Cav-1 deficiency (Cav-1-/- ) mice, and Cav-1-/- mice displayed wider alveolar septa, increased collagen deposition and more silicotic nodules. The mice peritoneal-derived macrophages were used to explore the role of Cav-1 in silica-induced inflammation, which plays a central role in mechanism of silicosis. Cav-1 inhibited silica-induced infiltration of inflammatory cells and secretion of inflammatory factors in vitro and in vivo, partly by downregulating NF-κB pathway. Additionally, silica uptake and expression of 4-hydroxynonenal in silicotic mice were observed, and it was found that Cav-1 absence triggered excessive silica deposition, causing a stronger oxidative stress response. These findings demonstrate the protective effects of Cav-1 in silica-induced lung injury, suggesting its potential therapeutic value in silicosis.

Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-ß/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-ß treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentially via suppression of TGF-ß/Smad2 and MAPK pathways.

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway.

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1ß, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

[Clinical value of biomarkers in diagnosis and treatment of idiopathic pulmonary fibrosis].

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia characterized by progressive accumulation of fibroblastic foci and destruction of the alveolar structure. Due to an incomplete understanding of the mechanism of the occurrence and progression of IPF, currently no effective means have been available for its early screening or treatment. With a poor overall prognosis, the patients with IPF have a median survival of only 2-4 years. In recent years, several studies have confirmed that dozens of molecules are involved in the development of IPF and can be used as potential biomarkers. These biomarkers play important roles in early diagnosis (such as SP-D, MMP-7, and osteopontin), prognostic evaluation (such as telomerase length, KL-6, mtDNA, HSP-70, LOXL2, CXCL13, miRNA, ICAM-1, and CCL18), and guiding treatment of IPF (such as TOLLIP rs3750920 genotype, SAMS score, and SP-D), and also provide potential therapeutic targets (such as TERT, TERR, RTEC, and PARN).

Clinical features and endemic trend of histoplasmosis in China: A retrospective analysis and literature review.

INTRODUCTION: Histoplasmosis is a rare mycosis with nonspecific clinical manifestation and a high misdiagnosis rate, which is an epidemic disease that occurred in several endemic areas. Cases of histoplasmosis were sporadic in China. OBJECTIVE: We detected the clinical characteristics and endemic trend of histoplasmosis to understand it more profoundly. METHOD: The clinical data of 34 cases of histoplasmosis hospitalized in Xiangya Hospital of Central South University from 2003 to 2016 were analyzed retrospectively. The relevant literature were reviewed roundly which were about histoplasmosis from 2001 to 2019 reported in the Chinese mainland. RESULTS: Thirty-four patients were included in the study, male predominance. About 44.1% were combined with underlying disease and HIV infection was observed in eight patients. Common clinical manifestations were fever (94.1%), followed by lymphadenopathy (70.6%) and anemia (67.6%). Organ involvement included lungs (52.9%), oral cavity (5.9%) and intestine (5.9%). Patients were diagnosed by bone marrow smears (44.1%), lymph node biopsy (41.1%), lung tissue biopsy (8.8%) and intestinal tissue biopsy (5.9%). About 70.6% received amphotericin B, while 38.2% received itraconazole therapy and 79.4% were improved. About 611 cases of histoplasmosis in the Chinese mainland were obtained in the study from the related literature, with 217 (37.0%) cases occurred in Yunnan province, 69 (11.9%) cases in Hunan province and 67 (11.6%) cases in Hubei province. All of them were high incidence area of histoplasmosis. CONCLUSION: Histoplasmosis is a rare mycosis with high diagnosis rate and has a prominent geographical distribution in China, which should be considered highly in clinical work.