Repeated inhalation of sevoflurane inhibits airway inflammation in an OVA-induced mouse model of allergic airway inflammation.

BACKGROUND AND OBJECTIVE: Repeated inhalation of sevoflurane (SVF) can benefit asthmatic patients by bronchodilation. However, the impact of repeated inhalation of SVF on allergic airway inflammation has not been clarified. This study was aimed at investigating the effects of repeated inhalation of SVF on airway inflammation in mice. METHODS: Female C57BL/6 mice were sensitized with ovalbumin (OVA) and treated by inhalation with SVF or vehicle daily for seven consecutive days, immediately followed by OVA challenge. Airway inflammation was evaluated by counting the numbers of different types of inflammatory infiltrates in bronchoalveolar lavage fluid (BALF), histology, cytokine measurements and mucus production in individual mice. RESULTS: In comparison with the OVA group, repeated inhalation of SVF significantly reduced the numbers of total cells, eosinophils, lymphocytes, macrophages and neutrophils (P < 0.05 to P < 0.01), and the levels of BALF tumour necrosis factor-α and lung high-mobility group box 1 (P < 0.01), accompanied by elevated levels of BALF interleukin-10 in allergic mice (P < 0.05). Repeat inhalation of SVF decreased the levels of serum OVA-specific immunoglobulin E (IgE) and mitigated allergic airway epithelial goblet cell hyperplasia and mucus hypersecretion in allergic mice (P < 0.01). CONCLUSIONS: Repeated inhalation of SVF inhibits allergic airway inflammation by reducing inflammatory infiltrates, improving the imbalance of cytokine responses and mitigating allergen-specific IgE responses and goblet cell hyperplasia in mice.

Successful steroid treatment for acute fibrinous and organizing pneumonia: A case report.

BACKGROUND: Since the acute fibrinous and organizing pneumonia (AFOP) was first described by Beasley in 2002, some case reports of patients aged from 38 d to 80 years have been published worldwide, but there is still no standard therapy for this disease and the treatment methods remain controversial. Both steroid and immunosuppressive agents, such as cyclophosphamide or mycophenolate mofetil, have been reported to be effective in some studies, but with many side effects, especially in patients of advanced age. CASE SUMMARY: We herein report an 81-year-old female patient who was admitted to our hospital due to dry cough, and breathlessness for 1 mo. She was treated with broad-spectrum antibiotics and anti-fungal therapy, but without improvement in both symptoms and radiological findings, and her respiratory status worsened, and she required bed rest almost the whole day. Computed tomography-guided percutaneous needle lung biopsy was performed and histopathology examination confirmed the diagnosis of AFOP. She was then successfully treated with a steroid monotherapy, which resulted in a satisfactory clinical outcome without serious complications. CONCLUSION: We conclude that complete remission of AFOP can be achieved by steroid monotherapy in patients of advanced age.

Mer receptor tyrosine kinase negatively regulates lipoteichoic acid-induced inflammatory response via PI3K/Akt and SOCS3.

Activation of toll-like receptor (TLR) signaling that initiates an innate immune response to pathogens must be strictly regulated to prevent excessive inflammatory damage in the host. Here, we demonstrate that Mer receptor tyrosine kinase (MerTK) is a negative regulatory molecule in the lipoteichoic acid (LTA)-induced inflammatory response. LTA that activated TLR2 signaling concomitantly induced activation of MerTK signaling in RAW264.7 macrophages, including phosphoinositide 3-kinase (PI3K)/Akt and suppressor of cytokine signaling 3 (SOCS3). Moreover, LTA induced MerTK activation in a time-dependent manner, and LTA-induced MerTK activation was dependent on the ligand Gas6. Additionally, pretreatment with a specific Mer-blocking antibody significantly inhibited LTA-induced phosphorylation of MerTK, while further enhancing LTA-induced phosphorylation of IκB-α and NF-κBp65 as well as production of TNF-α and IL-6. Meanwhile, the antibody blockade of MerTK markedly prevented LTA-induced Akt phosphorylation and SOCS3 expression, both of which were crucial for the inhibition of TLR2-mediated immune response. Collectively, these results suggest, for the first time, that MerTK is an intracellular negative feedback regulator that inhibits the inflammatory response of LTA-stimulated macrophages through the PI3K/Akt pathway and SOCS3 protein.

Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells.

Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α-dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation 'was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis.

TLR2 mediates phagocytosis and autophagy through JNK signaling pathway in Staphylococcus aureus-stimulated RAW264.7 cells.

Toll-like receptor 2 (TLR2) is involved in phagocytosis and autophagy to enhance host innate immune response to bacterial infection. TLR2 has been reported to participate in the recognition of Staphylococcus aureus (S. aureus). However, the role of TLR2 in phagocytosis and autophagy in S. aureus-stimulated macrophages and the underlying mechanisms as yet remain unclear. In the present study, stimulation of mouse macrophage cell line RAW264.7 with S. aureus activated multiple signaling pathways including mitogen-activated protein kinases (MAPKs), myeloid differentiation factor 88 (MyD88), phosphatidylinositide 3-kinase (PI3K) and Rac1 and triggered autophagy process. Knockdown of TLR2 by siRNA significantly reduced phagocytosis and autophagy of macrophages upon S. aureus infection. Interestingly, TLR2 siRNA markedly attenuated S. aureus-induced phosphorylation of c-Jun N-terminal kinase (JNK) but not p38 or extracellular regulated protein kinase (ERK) in macrophages. Similarly, SP600125, a JNK inhibitor, also down-regulated phagocytosis and autophagy in S. aureus-stimulated macrophages. Furthermore, TLR2 siRNA and SP600125 simultaneous treatment showed similar phagocytosis and autophagy compared to that in TLR2 siRNA treatment alone. Collectively, our results indicate that TLR2 may be critical for phagocytosis and autophagy through JNK signaling pathway, and provide an underlying mechanistic link between innate immune receptor and induction of phagocytosis and autophagy in S. aureus-stimulated macrophages.

Hypoxia down-regulates glucocorticoid receptor alpha and attenuates the anti-inflammatory actions of dexamethasone in human alveolar epithelial A549 cells.

AIMS: Glucocorticoids (GCs) are frequently used to treat various pulmonary diseases, which are typically accompanied by hypoxia. Whether hypoxia influences the effects of GCs on human airway cells remains unclear. The aim of the present study was to characterize changes in the expression levels of two isoforms of the glucocorticoid receptor (GR) and to evaluate the anti-inflammatory actions of GCs under hypoxic conditions in A549 cells. MAIN METHODS: A549 cells were exposed to normoxic or hypoxic conditions for 24, 48 and 72 h. Morphological alterations of cells were captured using a differential interference contrast microscope (DIC), and cell cycle distribution was estimated by flow cytometry. Real-time quantitative polymerase chain reaction and western blot were used to determine the mRNA and protein expression levels of GRalpha and GRbeta. Radioimmunoassay (RIA) for interleukin (IL)-8 was used to assess the anti-inflammatory actions of GCs after cells were stimulated with lipopolysaccharide (LPS). KEY FINDINGS: After cells were exposed to hypoxic conditions for 48 h, visible morphological alterations in the cells were observed. Cell cycle analysis showed that the number of cells in G1 phase increased significantly under hypoxia compared to the normoxic conditions. Hypoxia caused a time-dependent decrease in both mRNA and protein expression levels for GRalpha, but not GRbeta. Furthermore, when exposed to hypoxia for 48 h, the inhibitory effects of dexamethasone on LPS-stimulated IL-8 release were attenuated. SIGNIFICANCE: These results indicate that hypoxia impairs the anti-inflammatory actions of GCs in A549 cells, which could be attributed to down-regulation of GRalpha expression under hypoxic conditions.