Low-dose Exposure to Black Carbon and Cadmium Significantly Induce Lung Injury by Promoting Cellular Apoptosis

PMs has adverse biological effects on major living organs in the body, including lungs. The complex composition of PM2.5, including carbon black and heavy metals, cause toxic effects to the lung. The synergistic effects of CB and Cd were less investigated in previous study. In our research, we deciphered the combination of CBs and Cd enhanced the cytotoxicity in BEAS-2B cells in vitro and in vivo. In the molecular level, the intracellular level of Cd increased, as a result of the cell membrane damage, causing high expression of MT-1 in BEAS-2B cells. Moreover, the expression of BAX increased, and the expression of BCL-2 decreased. Collectively, our data suggests the apoptosis effect of synergistic effects of CB and Cd exposure.

Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling

Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were collected 24 h post LPS challenge. Results showed that glycine pretreatment attenuated LPS-induced decreases of mucin at both protein and mRNA levels, reduced LPS-triggered upregulation of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferons, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins. Further study showed that glycine-reduced LPS challenge resulted in the upregulation of nuclear factor κB (NF-κB), nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. In addition, LPS exposure led to the downregulation of NRF2 and downstream targets, which were significantly improved by glycine administration in the lung tissues. Our findings indicated that glycine pretreatment prevented LPS-induced lung injury by regulating both NLRP3 inflammasome and NRF2 signaling.

Anti-inflammatory Role of Trilobatin on Lipopolysaccharide-induced Acute Lung Injury through Activation of AMPK/GSK3β-Nrf2 Pathway

Inflammation is essential for the pathological process of acute lung injury (ALI). Trilo-batin, a glycosylated dihydrochalcone can show anti-oxidative and anti-inflammation properties. This study aimed to explore whether trilobatin could suppress inflammation in lipopolysaccharide (LPS)-induced ALI. Firstly, mice were injected with trilobatin intraperitoneally, and then LPS was administered intranasally to induce lung injury. Data from analysis of lung edema and pathologic histology of lung tissues indicated that pretreatment with trilobatin alleviated LPS-induced histopathological changes and decreased wet-to-dry weight (W/D) ratio. Moreover, LPS-induced lung injury was attenuated post trilobatin treatment with reduced protein concentration, cell numbers, neutrophils and macrophages in BALF (bronchoalveolar lavage fluid). Secondly, trilobatin treatment decreased the protein level of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) thereby suppressing LPS-induced inflammation. LPS-induced oxidative stress was ameliorated following trilobatin treatment with decreased malondialdehyde (MDA) and increased glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Lastly, trilobatin decreased NF-κB phosphorylation and increased Nrf2 through up-regulation of AMPK and GSK3β phosphorylation. In conclusion, trilobatin repressed oxidative stress and inflammatory damage by ameliorating LPS-induced ALI through activation of AMPK/GSK3β-Nrf2 and inhibition of NF-κB.

Using selective lung injury to improve murine models of spatially heterogeneous lung diseases

Many lung diseases, such as acute respiratory distress syndrome (ARDS), display significant regional heterogeneity, with patches of severely injured tissue adjacent to apparently healthy tissue. Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDS’s regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions, and precludes many regenerative medicine studies, since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies of current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used to track the location and extent of where the initial injury was, days later. Further, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves undamaged lung regions. Collectively, these attributes of CICSLI will allow better study of how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other lung diseases.

Ginsenoside Rh2 Ameliorates Lipopolysaccharide Induced Acute Lung Injury by Regulating the TLR4/ PI3K/Akt/mTOR, Raf-1/MEK/ERK and Keap1/Nrf2/HO-1 Signaling Pathways in Mice

The anti-inflammatory effect of ginsenoside Rh2 (GRh2) is one of the most important ginsenosides. The purpose of this study is to identify the anti-inflammatory and antioxidant effects of GRh2 after LPS challenge lung injury animal model. GRh2 reduced LPS-induced NO, TNF-α, IL-1, IL-4, IL-6 and IL-10 productions in lung tissues. GRh2 treatment decreased the histological alterations in the lung tissues and BALF protein content and total cells number also diminished in LPS-induced lung injury mice. Moreover, GRh2 blocked iNOS, COX-2, the phosphorylation of IκB-α, ERK, JNK, p38, Raf-1 and MEK protein expression which is corresponded to the growth of HO-1, Nrf-2, catalase, SOD and GPx expressions in LPS-induce lung injury. An experimental study has suggested that GRh2 has provided with anti-inflammatory effects in vivo, and its potential therapeutic efficacy in major anterior segment lung diseases.