Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation

Enzymes involved in collagen biosynthesis, including lysyl oxidase （LOX）, have been proposed as potential therapeutic targets for idio- pathic pulmonary fibrosis. LOX expression is significantly upregulated in bleomycin （BLM）-induced lung fibrosis, and knockdown of LOX expression or inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory ceU infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expres- sion of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung fibrosis. These results suggest that LOX is indispensable for the progression of BLM-induced experimental lung fibrosis by aggravating the inflammatory response and subse- quent fibrosis process after lung injury.     

"三伏贴"对慢性阻塞性肺病系统炎症的影响

目的:观察"三伏贴"对稳定期慢性阻塞性肺疾病(COPD)患者系统炎症的影响,并评价其有效性。方法:收集稳定期慢性阻塞性肺疾病患者60例,按随机数字表随机分为"三伏贴"治疗组与安慰剂治疗组,每组30例;在常规西医治疗的基础上,分别给予"三伏贴"和安慰剂贴敷治疗,分别在入伏、初伏、中伏及末伏进行4次穴位贴敷,完成1疗程治疗者共56例。观察治疗前、1个疗程结束时、治疗后3个月、治疗后6个月血清炎症因子的变化。应用酶联免疫吸附试验(ELISA)检测血清白细胞介素-8(IL-8),免疫比浊法测定血清CRP,比较治疗前后两组间的炎症因子变化趋势,同时比较治疗前后两组间CAT评分(COPD assessment test,CAT)、呼吸困难评分(MRC)及生存质量评分。结果:"三伏贴"组、安慰剂组血清IL-8、CRP随时间变化趋势不同;其中试验组血清炎症因子随时间呈逐渐下降趋势,但治疗后6个月时炎症因子略有升高,而安慰剂组炎症因子水平呈逐渐升高趋势,治疗前试验组与安慰剂组炎症因子水平差异无统计学意义,治疗3个月后,两组患者IL-8、CRP水平差异即有统计学意义(P0.05)。试验组患者治疗后CAT评分、MRC评分较治疗前下降,生存质量评分升高,差异有统计学意义(P0.05),而安慰剂组患者在治疗后CAT评分、MRC评分较治疗前升高,差异有统计学意义(P0.05),生存质量评分下降,差异有统计学意义(P0.05)。同一时间点,试验组较安慰剂组CAT评分、MRC评分下降,生存质量评分明显升高,差异有统计学意义(P0.05)。结论:冬病夏治穴位敷帖可以改善COPD患者生存质量,缓解症状,其作用机理可能与降低系统炎症相关因子有关。     

T lymphocytes and aortic aneurysms

Aortic aneurysms are common and life threatening problems with high rates of death. The initiation and progression of aneurysms are characterized by extensive extracellular matrix degradation and immune cells invasion within arterial wall. During the pathogenesis of all aneurysms, inflammation and immune cells play a significant role. Although T cells are abundant in aneurysm tissue, their functions in initiation and propagation of aneurysms remain unclear. This review summarizes the current state of knowledge of T lymphocytes on this disease and focuses on potential mechanisms of specific T cell responses.     

Maintenance of the enteric stem cell niche by bacterial lipopolysaccharides? Evidence and perspectives

The enteric nervous system (ENS) has to respond to continuously changing microenvironmental challenges within the gut and is therefore dependent on a neural stem cell niche to keep the ENS functional throughout life. In this study, we hypothesize that this stem cell niche is also affected during inflammation and therefore investigated lipopolysaccharides (LPS) effects on enteric neural stem/progenitor cells (NSPCs). NSPCs were derived from the ENS and cultured under the influence of different LPS concentrations. LPS effects upon proliferation and differentiation of enteric NSPC cultures were assessed using immunochemistry, flow cytometry, western blot, Multiplex ELISA and real‐time PCR. LPS enhances the proliferation of enteric NSPCs in a dose‐dependent manner. It delays and modifies the differentiation of these cells. The expression of the LPS receptor toll‐like receptor 4 on NSPCs could be demonstrated. Moreover, LPS induces the secretion of several cytokines. Flow cytometry data gives evidence for individual subgroups within the NSPC population. ENS‐derived NSPCs respond to LPS in maintaining at least partially their stem cell character. In the case of inflammatory disease or trauma where the liberation and exposure to LPS will be increased, the expansion of NSPCs could be a first step towards regeneration of the ENS. The reduced and altered differentiation, as well as the induction of cytokine signalling, demonstrates that the stem cell niche may take part in the LPS‐transmitted inflammatory processes in a direct and defined way.     

AnxA5 reduces plaque inflammation of advanced atherosclerotic lesions in apoE−/− mice

Annexin A5 (AnxA5) exerts anti‐inflammatory, anticoagulant and anti‐apoptotic effects through binding cell surface expressed phosphatidylserine. The actions of AnxA5 on atherosclerosis are incompletely understood. We investigated effects of exogenous AnxA5 on plaque morphology and phenotype of advanced atherosclerotic lesions in apoE^?/? mice. Advanced atherosclerotic lesions were induced in 12 weeks old Western type diet fed apoE^?/? mice using a collar placement around the carotid artery. After 5 weeks mice were injected either with AnxA5 (n = 8) or vehicle for another 4 weeks. AnxA5 reduced plaque macrophage content both in the intima (59% reduction, P < 0.05) and media (73% reduction, P < 0.01) of advanced atherosclerotic lesions of the carotid artery. These findings corroborated with advanced lesions of the aortic arch, where a 67% reduction in plaque macrophage content was observed with AnxA5 compared to controls (P < 0.01). AnxA5 did not change lesion extension, plaque apoptosis, collagen content, smooth muscle cell content or acellular plaque composition after 4 weeks of treatment as determined by immunohistochemistry in advanced carotid lesions. In vitro, AnxA5 exhibited anti‐inflammatory effects in macrophages and a flow chamber based assay demonstrated that AnxA5 significantly inhibited capture, rolling, adhesion as well as transmigration of peripheral blood mononuclear cells on a TNF‐α‐activated endothelial cell layer. In conclusion, short‐term treatment with AnxA5 reduces plaque inflammation of advanced lesions in apoE^?/? mice likely through interfering with recruitment and activation of monocytes to the inflamed lesion site. Suppressing chronic inflammation by targeting exposed phosphatidylserine may become a viable strategy to treat patients suffering from advanced atherosclerosis.     

Apoptosis drives cancer cells proliferate and metastasize

Cancer has been considered to be the result of accumulated gene mutations, which result in uncontrolled cell proliferations for a long time. Cancers are also regarded to be capable of immune evasion. Furthermore, resistance to apoptosis was recognized as an important trait of cancer in the last score of years. However, there are numerous paradoxical issues in this whole set of theory. For example, there is no known set of genes of which mutations are responsible for human cancers. As for the trait of ‘resistance to apoptosis’, the fact is that cancer has increased frequency of apoptosis. The more malignant the tumour is, the more apoptosis shows. In this study, we propose a new theory that apoptosis plays a key role in the malignant progression and metastasis of cancer. The growth of tumour is the difference between tumour cell proliferation and attrition plus the hyperplastic growth of stroma. Increased and unpreventable death caused by innate or environmental factors such as ischaemia and inflammation drives the tumour cells to proliferate relentlessly, move to new lands to establish colonies. In short, increased cell death is the origin of malignancy.     

Immune cells: plastic players along colorectal cancer progression

Inflammatory cells are involved in tumour initiation and progression. In parallel, the adaptive immune response plays a key role in fighting tumour growth and dissemination. The double‐edged role of the immune system in solid tumours is well represented in colorectal cancer (CRC). The development and progression of CRC are affected by the interactions between the tumour and the host's response, occurring in a milieu named tumour microenvironment. The role of immune cells in human CRC is being unravelled and there is a strong interest in understanding their dynamics as to tumour promotion, immunosurveillance and immunoevasion. A better definition of immune infiltration would be important not only with respect to the ‘natural history’ of CRC, but in a clinically relevant perspective in the 21st century, with respect to its post‐surgical management, including chemotherapy responsiveness. While it is becoming established that the amount of tumour‐infiltrating lymphocytes influences the post‐surgical progression of early‐stage CRC, the relevance of this immune parameter as to chemotherapy responsiveness remains to be clarified. Despite recent experimental work supporting the notion that infiltrating immune cells may influence chemotherapy‐mediated tumour cell death, tumour‐infiltrating cells are not employed to identify patients who are more likely to benefit from adjuvant treatment. This review focuses on studies addressing the role of innate and adaptive immune cells along the occurrence and the progression of potentially curable CRC.     

Cooperative role of endogenous leucotrienes and platelet‐activating factor in ischaemia–reperfusion‐mediated tissue injury

Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B₄, cysteinyl‐LTs (CysLTs) and platelet‐activating factor (PAF). Yet, their potentially cooperative role in regulating I/R‐mediated inflammation has not been thoroughly assessed. The present study aimed to determine the cooperative role of lipid mediators in regulating PMN migration, tissue oedema and injury using selective receptor antagonists in selected models of I/R and dermal inflammation. Our results show that rabbits, pre‐treated orally with BIIL 284 and/or WEB 2086 and MK‐0571, were protected from remote tissue injury following I/R or dermal inflammation in an additive or synergistic manner when the animals were pre‐treated with two drugs concomitantly. The functional selectivity of the antagonists towards their respective agonists was assessed in vitro, showing that neither BIIL 284 nor WEB 2086 prevented the inflammatory response to IL‐8, C5a and zymosan‐activated plasma stimulation. However, these agonists elicited LTB₄ biosynthesis in isolated rabbit PMNs. Similarly, a cardioprotective effect of PAF and LTB₄ receptor antagonists was shown following myocardial I/R in mice. Taken together, these results underscore the intricate involvement of LTB₄ and PAF in each other's responses and provide further evidence that targeting both LTs and PAF receptors provides a much stronger anti‐inflammatory effect, regulating PMN migration and oedema formation.