Acute 1-NP exposure induces inflammatory responses through activating various inflammatory signaling pathways in mouse lungs and human A549 cells.

1-Nitropyrene (1-NP), a key component of fine particulate matter (PM2.5), is a representative of nitrated polycyclic aromatic hydrocarbons (NPAHs). The aim of this research is to investigate proinflammatory effects of acute 1-NP exposure in mouse lungs and human A549 cells. All mice except controls were intratracheally instilled with 1-NP (20 µg/mouse). A549 cell, a human lung cancer cell line, was cultured with or without 1-NP (5 µM). Acute 1-NP exposure elevated lung weight and caused infiltration of inflammatory cells, especially neutrophils in mouse lungs. Although it had little effect on serum TNF-α and KC, acute 1-NP exposure elevated the levels of TNF-α and KC in BALF. Correspondingly, acute 1-NP exposure upregulated pulmonary Il-1ß, Il-6, Tnf-α and Kc. Mechanistically, acute 1-NP exposure activated nuclear factor kappa B (NF-κB) in mouse lungs and human A549 cells. Additionally, acute 1-NP exposure induced Akt phosphorylation in mouse lungs and human A549 cells. Moreover, acute 1-NP exposure induced phosphorylation of pulmonary JNK and ERK1/2, molecules of the mitogen-activated protein kinase (MAPK) pathway. This study provides evidence that acute 1-NP exposure induces inflammatory responses through activating various inflammatory signaling pathways in mouse lungs and human A549 cells.

Vitamin D deficiency exacerbates bleomycin-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated epithelial-mesenchymal transition.

BACKGROUND: Our earlier report indicated that active vitamin D3 inhibited epithelial-mesenchymal transition (EMT) in bleomycin (BLM)-induced pulmonary fibrosis. The objective of this study was to further investigate whether vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis. METHODS: This study consists of two independent experiments. Experiment 1, male mice were fed with vitamin D deficient (VDD) fodder. Experiment 2, Cyp27b1+/+, Cyp27b1+/- and Cyp27b1-/- mice were fed with standard diet. For pulmonary fibrosis, mice were intratracheally instilled with a single dose of BLM (1.5 mg/kg). Serum 25(OH) D level was measured. Pulmonary collagen deposition was assessed by Sirius red staining. EMT was measured and transforming growth factor-beta (TGF-ß)/Smad3 signaling was evaluated in the lungs of BLM-treated mice. RESULTS: The relative weight of lungs was elevated in BLM-treated mice. Col1α1 and Col1α2, two collagen protein genes, were upregulated, and collagen deposition, as determined by Sirius red staining, was observed in the lungs of BLM-treated mice. E-cadherin, an epithelial marker, was downregulated. By contrast, vimentin and α-SMA, two EMT markers, were upregulated in the lungs of BLM-treated mice. Pulmonary TGF-ß/Smad3 signaling was activated in BLM-induced lung fibrosis. Further analysis showed that feeding VDD diet, leading to vitamin D deficiency, aggravated elevation of BLM-induced relative lung weight. Moreover, feeding VDD diet aggravated BLM-induced TGF-ß/Smad3 activation and subsequent EMT in the lungs. In addition, feeding VDD diet exacerbated BLM-induced pulmonary fibrosis. Additional experiment showed that Cyp27b1 gene knockout, leading to active vitamin D3 deficiency, exacerbated BLM-induced pulmonary fibrosis. Moreover, Cyp27b1 gene knockout aggravated pulmonary TGF-ß/Smad2/3 activation and subsequent EMT in BLM-induced lung fibrosis. CONCLUSION: Vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated EMT in the lungs.

Candida albicans-induced acute lung injury through activating several inflammatory signaling pathways in mice.

Candida albicans infection-induced acute lung injury is one of the most prevalent diseases in immunosuppressive individual. Nevertheless, the mechanism by which Candida albicans induced acute lung injury remains unclear. The present study investigated the mechanism by which Candida albicans induced acute lung injury in mice. Mice were randomly divided into four groups and intratracheally injected with 60 µl Candida albicans (106 CFU) or normal saline. Half of the mice were sacrificed at 6 h after Candida albicans. The rest of the mice for survival test were observed until 7 d after Candida albicans. As expected, immunosuppression aggravated Candida albicans-induced acute lung injury and death in mice. Additionally, Candida albicans infection elevated mRNA levels of pro-inflammatory and chemokines in lungs and the levels of IL-6, IL-1ß and IL-17 in serum. Further study showed that Candida albicans promoted nuclear translocation of NF-κB p50 and p65 subunits in pulmonary epithelial cells and interstitial cells. Candida albicans induced pulmonary p38, ERK1/2 and Akt phosphorylation in normal and immunosuppressive mice. Moreover, Candida albicans infection activated pulmonary STAT3 signaling in normal and immunosuppressive mice. Overall, these results suggest that Candida albicans induced acute lung injury and death may be through activating several inflammatory signaling pathways.