Research progress in role and mechanism of damage-associated molecular patterns in lung injury after acute spinal cord injury / 中华创伤杂志

Acute spinal cord injury（ASCI），commonly seen in spinal surgery，is usually caused by mechanical injury to the spine. ASCI can lead to secondary lung injury and even acute respiratory distress syndrome（ARDS），seriously endangering the life safety of patients. Damage-associated molecular pattern（DAMP）is a sort of endogenous substances released after injury，including intracellular proteins，extracellular matrix，secretory factors and nucleic acid-related products. DAMP released after ASCI activates downstream signaling pathways and participates in lung injuries. DAMP-related studies have revealed molecular mechanism of lung injury after ASCI，and explored the possible therapeutic targets of lung injury. In this study，the authors review the mechanism of action of DAMP in lung injury after ASCI and the role of different kinds of DAMP in lung injury，so as to provide new ideas for clinical treatment of lung injury after ASCI.

Advance in mechanism study of inflammation in post-ischemic stroke and opportunity of new drug development / 中国药理学通报

Inflammation mediated by the damage-associated molecular patterns (DAMPs) moleculesdominates the pathological process of ischemic stroke in the middle and late stages. In this process, the activation of immune cells and subsequent production of various inflammatory cytokines, chemokines and other cytotoxic mediators are the key factors that trigger inflammation injuries after ischemia. Meanwhile, this mechanism also induces the formation of immune cells with anti-inflammatory activities and tissue repair properties, boosting the regeneration of damaged never system. DAMPs-TLR-NF-κB inflammatory activation chain as the main axis of new anti-stroke drug approaches has become a direction to explore the novel treatments of stroke, which also provides a rational basis for anti-inflammatory therapy in clinical practice for stroke patients. In this paper, we highlighted the current status on the mechanism study with focus on the activation chain of macrophage and microglia involved in DAMPs-TLR-NF-κB in inflammation after stroke and discussed the future development in searching the potential new treatments and therapeutic agents which could be applied in clinics.

Helicobacter Pylori Infection and Lung Cancer: New Insights and Future Challenges / 中国肺癌杂志

Helicobacter pylori (H. pylori) is the causative agent of chronic gastritis and peptic ulcer diseases and is an important risk factor for the development functional dyspepsia, peptic ulceration, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H. pylori has very high rates of infection in human populations, and it is estimated that over 50% of the world population is infected. Recently, certain extra-gastric manifestations, linked to H. pylori infection, have been widely investigated. Noteworthy, a growing body of evidences supports an association between H. pylori infection with lung cancer. The present review intend to highlight not only the most recent evidences supporting this association, but also some missed points, which must be considered to validate this emerging association.

Damage-Associated Molecular Patterns in Inflammatory Diseases

Damage-associated molecular patterns (DAMPs) are endogenous danger molecules that are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors (PRRs). Although DAMPs contribute to the host's defense, they promote pathological inflammatory responses. Recent studies have suggested that various DAMPs, such as high-mobility group box 1 (HMGB1), S100 proteins, and heat shock proteins (HSPs), are increased and considered to have a pathogenic role in inflammatory diseases. Here, we review current research on the role of DAMPs in inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and cancer. We also discuss the possibility of DAMPs as biomarkers and therapeutic targets for these diseases.

Advances in the study of NETs in the pathogenesis of chronic obstructive pulmonary disease / 医学研究生学报

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic inflammatory disease of the lung in the worldwide. With the deeper development of the study, people gradually realized that COPD also with the characteristics of autoimmune diseases. However, the initiation mechanism of acquired immunity in COPD is still unclear. Chronic neutrophilic inflammation of the airways is a distinct feature of COPD. The latest research shows that neutrophils can form a reticular substance composed of DNA in the infected state-NETs, which can not only give full play to the anti infection effect, but also cause tissue damage. In some autoimmune diseases, it can even initiate the acquired immune responses. This paper will briefly review the recent advances of NETs in the pathogenesis of COPD and its potential role as an anti-inflammatory target for COPD, so as to provide new ideas for the anti-inflammatory treatment of COPD in the future.

Protective effect of MCC950 against lung injury induced by mitochondrial damage-associated molecular patterns / 医学研究生学报

Objective There is still no specific immuno-therapy to acute respiratory distress syndrome induced by severe trau-ma.The article aimed to investigate the effect of MCC 950 on lung in-jury induced by mitochondrial damage-associated molecular patterns ( MTDs) and preliminarily evaluate its molecular mechanism . Methods 40 SD rats were randomly devided into control group , MTDs group, MCC950 group, MTDs+MCC950 group.The rats were were taken MCC950 (20mg/kg) by peritoneal injection pretreatment for 1 hour, followed by tail vein injection of MTDs (5%liver vol-ume) and were killed 12 hours later.ELISA were applied to detect tumor necrosis factor (TNF-α), interleukin-1β( IL-1β) and IL-18 in broncho-alveolar lavage fluid ( BALF) , and BCA method to assess the content of total protein .Lung tissues were weighed to calculate lung wet weight/body weight( LWW/BW) ratio, and stained by HE staining to observe the pathological changes through light micro -scope.Smith lung injury score was used to assess histological lung injury .Western blot was employed to evaluate the protein expression of Pro-Caspase-1 and Caspase-1. Results ①Compared with control group , TNF-α, IL-1βand IL-18 in BALF of MTDs group were significantly increased( all P<0.05), but not in MCC950 group(P>0.05), TNF-αin BALF of MTDs +MCC950 group were signifi-cantly increased( all P<0.05), IL-1βand IL-18 were not(all P>0.05).Compared with MTDs group, IL-1βand IL-18 in BALF of MTDs +MCC950 group were in serious decline (all P<0.05).Compared with control group, the LWW/BW ratio [(4.19±0.36)mg/g vs (6.32±0.54)mg/g, P<0.05] and the content of total protein [(0.12±0.03)g/L vs (0.79±0.07)g/L, P<0.05] were dramatically increased.Compared with MTDs group, the LWW/BW ratio [(4.35±0.29)mg/g, (4.47±0.0.46)mg/g, P<0.05] and the content of total protein [(0.12±0.06)g/L, (0.15±0.06)g/L, P<0.05] were in serious decline.Smith lung injury score revealed that compared with control group the score of MTDs group was elevated (1.00±0.00 vs 8.33±0.58, P<0.05), and the score of MTDs+MCC950 group was significantly decreased than MTDs group ( 8.33±0.58 vs 3.67±0.58, P<0.05) .Compared with control group , the protein expres-sion of Pro-caspase-1 and caspase-1 were markedly improved (all P<0.05).However, the expression of caspase-1 was significantly milder than that in MTDs group ( P<0.05), the protein expression of Pro-caspase-1 was comparable ( P>0.05). Conclusion MCC950 exerts protective effect against lung injury induced by MTDs probably via the inhibition of NLRP 3 inflammasome activation .

Current Pathological and Laboratory Considerations in the Diagnosis of Disseminated Intravascular Coagulation

Systemically sustained thrombin generation in vivo is the hallmark of disseminated intravascular coagulation (DIC). Typically, this is in response to a progressing disease state that is associated with significant cellular injury. The etiology could be infectious or noninfectious, with the main pathophysiological mechanisms involving cross-activation among coagulation, innate immunity, and inflammatory responses. This leads to consumption of both pro- and anticoagulant factors as well as endothelial dysfunction and disrupted homeostasis at the blood vessel wall interface. In addition to the release of tissue plasminogen activator (tPA) and soluble thrombomodulin (sTM) following cellular activation and damage, respectively, there is the release of damage-associated molecular patterns (DAMPs) such as extracellular histones and cell-free DNA. Extracellular histones are increasingly recognized as significantly pathogenic in critical illnesses through direct cell toxicity, the promotion of thrombin generation, and the induction of neutrophil extracellular trap (NET) formation. Clinically, high circulating levels of histones and histone–DNA complexes are associated with multiorgan failure, DIC, and adverse patient outcomes. Their measurements as well as that of other DAMPs and molecular markers of thrombin generation are not yet applicable in the routine diagnostic laboratory. To provide a practical diagnostic tool for acute DIC, a composite scoring system using rapidly available coagulation tests is recommended by the International Society on Thrombosis and Haemostasis. Its usefulness and limitations are discussed alongside the advances and unanswered questions in DIC pathogenesis.

NETosis in Autoimmune Diseases

Neutrophils are the major antimicrobial cells of the innate immune system, which are recruited rapidly to the sites of infection and provide the primary defense against pathogens. Recent evidence suggests that neutrophils undergo a distinct cell death mechanism called NETosis, which not only contributes to the host defense, but also leads to severe pathological immune responses in cases of dysregulation. Here, we review the general features of NETosis as well as the generation of autoantigens and damage-associated molecular patterns by NETosis in autoimmune diseases. This review discusses the pathogenic role of NETosis in rheumatoid arthritis and systemic lupus erythematosus, where neutrophils may play a key role in the pathogenesis of these diseases, and suggest the possibility of neutrophil extracellular traps as biomarkers and therapeutic targets for the treatment of autoimmune diseases.

Effect of lipopolysaccharide on toll like receptor 7 and toll like receptor 9 in AR42J cell lines / 中华胰腺病杂志

Objective To investigate the roles of toll like receptor7 (TLR7) and toll like receptor 9 (TLR9) in the pathogenesis of acute pancreatitis.Methods AR42J cells were treated by lipopolysaccharide at different dosages (0,1,10,100 mg/L),and cell model of acute pancreatitis in vitro was established.AR42J cells without lipopolysaccharide treatment were as control.Cells and culture supernatant were collected after 24 hours cultivation.TLR7,TLR9 mRNA and protein expressions were detected by RT-PCR and Western Blot,and levels of TNF-α,IL-10 in culture supernatant were measured by ELISA.Results The TLR 7 mRNA expression levels in control group,1,10,100 mg/L lipopolysaccharide group were 0.12 ± 0.09,0.28 ± 0.06,0.49 ± 0.04,0.78 ± 0.04,and the TLR9 mRNA expression levels were 0.06 ± 0.02,0.32 ± 0.03,0.56 ± 0.14,0.84 ± 0.12; the TLR7 protein expression levels were 0.04 ± 0.01,0.26 ± 0.05,0.49 ±0.04,0.77 ±0.16,and the TLR9 protein expression levels were 0.10 ±0.14,0.62 ±0.23,1.21 ± 0.26,1.75 ± 0.13 ; the TNF-α levels in culture supernatant were (8.01 ± 5.32),(25.64 ± 8.71),(49.06 ± 10.23),(75.83 ± 6.65) ng/L,and the IL-10 levels were (155.54 ± 25.47),(105.16 ± 10.49),(69.36 ± 8.19),(14.07 ± 9.06)ng/L.The expression levels of TLR7 and TLR9's mRNA,protein in cell,as well as the levels of TNF-α in culture supernatant increased with the lipopolysaccharide concentration,while the levels of IL-10 in culture supernatant decreased with the lipopolysaccharide concentration,and the difference among these groups was statistically significant (P ＜ 0.01).Conclusions The expressions of TLR7 and TLR9 in AR42J cells treated by using lipolysaccharide are obviously up-regulated,and it suggests that TLR7 and TLR9 may be vital in the pathogenesis of acute pancreatitis.