S100A9 as a novel diagnostic and prognostic biomarker in human gastric cancer

Abstract

Objective: The morbidity and mortality of gastric cancer (GC) is high, but there are lack of the biomarkers for early diagnosis and progression of GC. We aimed to identify a novel biomarker for the growth and progression of GC.

Methods: The Cancer Genome Atlas (TCGA) database including 352 eligible patients was used to screen candidate genes related to the prognosis of GC. A proteomics analysis of Chinese Human Proteome Sketches (CHPS) including 84 eligible sample tissues was conducted to further identify candidate biomarkers. A series of in vitro assays were performed to investigate the functions of candidate proteins in GC. Next, to verify whether the candidate oncogene was associated with gastric carcinogenesis, we screened its expression levels using samples from 200 patients with chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia, or GC and healthy controls.

Results: According to the analyses of the TCGA database and CHPS, we found that S100A9 may be associated with the prognosis of GC. The results of proliferation, wound-healing and invasion assays, immunohistochemistry (IHC) and western blot showed that high levels of S100A9 in tissues were significantly associated with GC aggressiveness and a poor prognosis (p?<?.05). Furthermore, we found that the expression of S100A9 increased gradually during the process of gastric carcinogenesis (p?<?.05). The diagnostic sensitivity and specificity of S100A9 as a biomarker for early GC were 61.4% and 81.3%, respectively.

Conclusions: This study reveals that S100A9 may be a novel biomarker for the early diagnosis and prognosis of GC patients.     

外周血钙卫蛋白、环氧化酶-2水平变化与动脉血栓性疾病的关系

目的 探讨外周血钙卫蛋白（S100A8/A9）、环氧化酶-2（COX-2）水平与动脉血栓性疾病的关系及其临床意义.方法 选取动脉血栓性疾病患者101例,其中急性心肌梗死患者50例,冠心病患者51例.25例健康体检者为对照组.采用酶联免疫吸附法（ELISA）检测各组血清S100A8/A9、COX-2水平,并分析S100A8/A9、COX-2水平间的相关性.结果 （1）动脉血栓性疾病患者外周血S100A8/A9、COX-2水平明显高于对照组;（2）急性心肌梗死组患者S100A8/A9、COX-2水平明显高于冠心病组;（3）急性心肌梗死组和冠心病组S100A8/A9水平与COX-2水平均无明显相关性.结论 心血管病患者外周血S100A8/A9、COX-2水平明显升高可能与疾病的发生、发展相关;S100A8/A9、COX-2可作为判断动脉血栓性疾病严重程度的参考指标之一.     

S100A8和S100A9在冠心病中的研究进展

S100A8和S100A9作为内源性危险相关分子模式与Toll样受体4和晚期糖基化终产物受体相识别,通过参与免疫应答,改变内皮通透性并促进斑块内炎症,从而影响动脉粥样硬化的发生和发展.此外,S100A8和S100A9血浆水平升高与增加心血管事件的风险密切相关.本文综述S100A8和S100A9的研究现状及其在冠心病的预...     

S100A8 enhances IL-1β production from nasal epithelial cells in eosinophilic chronic rhinosinusitis

BackgroundChronic rhinosinusitis is classified into eosinophilic chronic rhinosinusitis (ECRS) and non-eosinophilic chronic rhinosinusitis (NECRS). ECRS is a refractory allergic disease involving a variety of immune and epithelial cells. S100A8 is a damage-associated molecular pattern that is closely related to allergic inflammation. However, the pathological implications of S100A8 in ECRS have not been clarified.MethodsWe evaluated the role of S100A8 in the pathogenesis of ECRS. Gene expression profiles of nasal polyps obtained from patients with ECRS or NECRS were evaluated using RNA sequencing.ResultsS100A8 was identified as a significantly upregulated gene in nasal polyps associated with ECRS. Immunohistochemistry consistently revealed intense S100A8 staining in nasal polyps from patients with ECRS. Human nasal epithelial cells expressed the receptor for advanced glycation end products and Toll-like receptor 4. Recombinant S100A8 protein induced interleukin-1β secretion in human nasal epithelial cells.ConclusionsOur data demonstrate that S100A8 results in production of interleukin-1β in the nasal epithelium, which may be involved in the pathogenesis of ECRS.     

Expression and clinical significance of S100A2 and p63 in esophageal carcinoma

AIM： TO investigate the expression and clinical significance of S100A2 mRNA and protein, p63 protein in esophageal squamous cell carcinoma （ESCC） and their roles in carcinogenesis and progression of esophageal carcinoma （EC）. METHODS： Immunohistochemical staining （S-P method） for S100A2 and p63 protein were performed in 40 samples of ESCC and 40 samples of normal esophageal mucosa. In situ hybridization （ISH） was used to detect the expression of S100A2 mRNA. RESULTS： Expression of S100A2 mRNA in ESCC was positive in 77.5% of samples, which was lower than that in normal mucosa （100%） by ISH （P = 0.002）. The expression level of S100A2 mRNA was closely related to differentiation and and node-metastasis （P = 0.012, P = 0.008）. Expression of $100A2 protein was positive in 72.5% of ESCC samples and expression of p63 protein was positive in 37.5% of ESCC samples, and was lower than that in normal mucosa （100%） （P = 0.000）. The expression of S100A2 protein was correlated with the differentiation and node-metastasis （P = 0.007, P = 0.001）, but no relationship was observed between the expression of p63 protein and clinical pathological manifestations. S100A2 protein was positively correlated with the expression of S100A2 mRNA, and negatively associated with the expression of p63 protein （P = 0.000, P = 0.002）. CONCLUSION： S100A2 and p63 protein both play important roles in the carcinogenesis of ESCC. An investigation into the combined expression of S100A2 and p63 may be helpful in early diagnosis and in evaluating the prognosis of ESCC.     

胰腺癌S100A4癌基因及ppENK抑癌基因的甲基化状态

目的 分析胰腺癌及胰腺癌细胞株ppENK、S100A4基因的甲基化状态.方法 收集31例胰腺癌及相应癌旁组织、5株胰腺癌细胞株及1例正常胰腺组织.采用MSP方法分析ppENK基因甲基化状态,采用COBRA方法分析S100A4基因甲基化状态,RT-PCR检测ppENK和S100A4 mRNA,免疫组化法检测S100A4蛋白表达,并与胰腺癌临床参数进行相关性分析.结果 正常胰腺组织ppENK基因无甲基化,S100A4基因高甲基化.31例胰腺癌组织中ppENK基因甲基化率为90.3%,与临床参数无相关性;S100A4基因低甲基化率为71.0%,仅与外周血CA19-9水平呈相关性(P=0.011,OR=0.05).S100A4蛋白在胰腺癌组织中表达率为87.1%,该表达与S100A4基因低甲基化相关(P=0.017),同时与肿瘤的分化程度有关,肿瘤分化程度越低,表达阳性率越高.S100A4基因低甲基化与ppENK基因甲基化相关(P=0.019).5株胰腺癌细胞株ppENK基因均甲基化,ppENK mRNA不表达;S100A4基因均低甲基化,S100A4 mRNA均高表达.结论 胰腺癌组织ppENK基因为高甲基化状态,而S100A4基因为低甲基化状态.     

胆管细胞癌组织S100A6 mRNA及其蛋白表达变化*

目的 检测胆管癌组织S100A6 mRNA及其蛋白表达的变化。方法 在40例胆管癌患者和40例胆道良性疾病,分别取胆管癌组织、癌旁组织和肝组织,检测S100A6 mRNA及其蛋白表达变化,采用ELISA法测定血清S100A6水平。应用单因素和多因素非条件Logistic回归分析造成胆管癌患者血清S100A6高水平的危险因素。结果 在40例癌旁组织和肝组织中,S100A6蛋白分别阳性8例（20%）和12例（30%）,显著低于肝内胆管癌组织的26例（65%,P<0.05）;癌旁组织和肝组织S100A6 mRNA相对水平分别为（0.92±0.33）和（1.12±0.46）,显著低于肝内胆管癌组织的【（1.93±0.57）,P<0.05】;癌旁组织和肝组织S100A6蛋白相对表达量分别为（0.56±0.16）和（0.85±0.46）,显著低于肝内胆管癌组织的【（1.63±0.51）,P<0.05】;肝内胆管癌患者血清S100A6水平为（2456.85±128.31）pg/ml,显著高于对照组的（2234.26±116.35）pg/ml（P<0.05）;S100A6与CEA、CRP、浸润深度、淋巴结转移、TNM分期、肿瘤分化程度呈正相关（P<0.05）;多因素Logistic回归分析显示,肿瘤浸润深、淋巴结转移、TNM分期和细胞分化差是造成肿瘤患者血清S100A6高水平的危险因素（P<0.05）。结论 血清S100A6高水平的意义还有待于进一步研究。     

Protéines S100A8, S100A9 et S100A12 : marqueurs inflammatoires ou acteurs physiopathologiques de la polyarthrite rhumatoïde

Although S100 proteins represent 40% of the neutrophil cytoplasmic proteins, their physiological and pathological functions are still unclear. S100A8, S100A9 and S100A12 protein concentrations are dramatically enhanced in synovial fluid and synovium of patients suffering from rheumatoid arthritis. Their expression seems to correlate with disease activity and joint damage. These proteins are likely involved in rheumatoid arthritis pathogenesis by enhancing extracellular matrix proteolysis, autoimmunity and inducing the pseudotumoral phenotype of the synoviocytes in rheumatoid arthritis. S100A8, S100A9 and S100A12 assessment will probably constitute a relevant tool for rheumatoid arthritis diagnosis and will improve inflammatory arthritides management.     

Prediction of long-term remission of oligo/polyarticular juvenile idiopathic arthritis with S100A12 and vascular endothelial growth factor

Objectives: This study aimed to evaluate the usefulness of S100A12 and vascular endothelial growth factor (VEGF) for predicting the stability of remission for discontinuing methotrexate (MTX) and/or biological agents in Japanese patients with oligo/polyarticular juvenile idiopathic arthritis (JIA).

Methods: Forty-four patients with oligo/polyarticular JIA who received MTX with or without biological agents were enrolled. Serum concentration of both S100A12 and VEGF were simultaneously evaluated by ELISA in active and in remission phase determined by activity markers including DAS-28.

Results: S100A12 and VEGF were correlated with DAS-28. Of the 22 patients with oligo/polyarticular JIA in clinical remission, 13 patients with low S100A12 and VEGF concentrations could discontinue treatment without relapse over 2 years. However, nine patients without low S100A12 and VEGF concentrations relapsed afterwards, even though they had been in clinical remission. The cut-off levels of S100A12 and VEGF for division into two groups of the maintenance remission and relapse groups were 177 ng/ml and 158 pg/ml, respectively.

Conclusions: S100A12 and VEGF are useful markers for assessing disease activity of oligo/polyarticular JIA in remission phase. These markers should be kept low when clinicians consider tapering or discontinuing treatments in oligo/polyarticular JIA patients.     

Alcohol intoxication inhibits pulmonary S100A8 and S100A9 expression in rats challenged with intratracheal lipopolysaccharide

BACKGROUND: Alcohol is known to inhibit the recruitment of polymorphonuclear leukocytes (PMNs) into tissue sites including the lung. During infection and inflammation, recruited neutrophils (PMNs) release S100 proteins that function to promote the recruitment of additional phagocytes. METHODS AND RESULTS: This study investigated the effects of alcohol intoxication on S100 protein production in the lung in response to lipopolysaccharide (LPS). Animals were administered alcohol (5.5 g/kg) or saline 30 minutes before intratracheal challenge with LPS (100 microg/rat). Alcohol suppressed PMN recruitment into the lung following intratracheal LPS, which was associated with an inhibition of increase in S100A8 levels in both the bronchoalveolar lavage (BAL) fluid and lysates of cells recovered by BAL at 90 minutes and 4 hours post-LPS challenge. S100A8 and S100A9 mRNA expression in cells recovered by BAL was significantly up-regulated at both 90 minutes and 4 hours after the LPS challenge, and alcohol also suppressed this response. In addition, intratracheal LPS caused a transient increase in S100A8 mRNA expression in circulating leukocytes at 90 minutes after the challenge. Similarly, this LPS-induced up-regulation of S100A8 mRNA expression was inhibited in rats intoxicated with alcohol. CONCLUSION: These data show that alcohol inhibits the S100 protein response in the lung, which may serve as a mechanism underlying alcohol-induced suppression of PMN recruitment into the terminal airways during pulmonary infection.     

Serum and mucosal S100 proteins, calprotectin (S100A8/S100A9) and S100A12, are elevated at diagnosis in children with inflammatory bowel disease

OBJECTIVE: Various markers characterize the complex inflammatory processes seen in chronic inflammatory bowel disease (IBD) including calprotectin, a complex of two S100 proteins, which has been evaluated and validated as a faecal marker of inflammation. However, the systemic and mucosal expression patterns of calprotectin and related S100 proteins are not well characterized in this disease. The objective of this study was to assess serum and mucosal levels of calprotectin, S100A12 and soluble receptor for advanced glycation end products (sRAGE), a putative S100 ligand, in a paediatric population with IBD. MATERIAL AND METHODS: Children were enrolled at diagnosis of IBD, along with groups of children without IBD. Standard inflammatory markers and disease activity scores were collated. Calprotectin, S100A12 and sRAGE levels in serum and biopsy culture supernatants were measured by ELISA and tissue distribution of S100 proteins was investigated by immunohistochemistry. RESULTS: Serum and mucosal calprotectin and S100A12 levels were increased in children with IBD as compared with non-IBD controls. Serum calprotectin levels correlated with S100A12 levels and with disease activity scores in children with IBD. sRAGE levels were not increased in IBD. S100A8, S100A9 and S100A12 were abundantly expressed throughout the lamina propria and epithelium in inflamed mucosa. In contrast, these proteins were present in the lamina propria, but not the epithelium, in non-inflamed mucosa. CONCLUSIONS: Serum calprotectin and S100A12 are increased in children with IBD and indicate disease activity. Elevated levels of these proteins are present in the colonic mucosa and may contribute to the pathogenesis of IBD. Furthermore, an imbalance between sRAGE and S100A12 may contribute to inflammatory changes present in IBD.     

Fecal S100A12: a novel noninvasive marker in children with Crohn's disease

BACKGROUND: The calcium-binding protein S100A12 is related to calprotectin, a protein shown to be a useful marker of gut inflammation. S100A12 levels are elevated in serum and mucosa of children with inflammatory bowel disease (IBD) and may be implicated in the pathogenesis of IBD. The aims of this study were to validate an immunoassay for the detection of fecal S100A12, to assess its value as a new noninvasive marker of gut inflammation, and to investigate S100A12 levels in feces of children with IBD at diagnosis and during treatment. MATERIALS AND METHODS: Feces were collected from children with active IBD at diagnosis and during treatment for IBD and from normal healthy control subjects. Fecal and serum levels of S100A12 were measured by immunoassay. RESULTS: A sensitivity of 96% and a specificity of 92% were observed when 10 mg/kg fecal S100A12 was used as a cutoff. S100A12 levels were evenly distributed throughout fecal samples and were stable for 7 days when stored at room temperature. Fecal S100A12 was elevated in children with IBD compared with healthy control subjects, with levels closely correlated to disease activity and other serum inflammatory markers, particularly lower gut involvement. Fecal S100A12 levels fell during therapy in children entering remission with normal C-reactive protein levels. CONCLUSIONS: Fecal S100A12 is a novel noninvasive marker that distinguishes children with active IBD from healthy control subjects with high sensitivity and specificity. Fecal S100A12 possesses characteristics that are desirable for a noninvasive disease marker and therefore is a suitable candidate marker for IBD. Further evaluation is required to examine this marker in additional contexts.     

血清S100A12蛋白与克罗恩病活动性的相关研究

目的:研究血清S100A12蛋白水平在克罗恩病(CD)患者中的表达及其与CD活动性的关系。方法:选取44例确诊为CD的患者为研究对象,计算CD活动指数(CDAI),按照CDAI分为活动期CD患者和缓解期CD患者。同时选取16例非消化道感染的患者作为感染对照组,15名健康体检者作为正常对照组。用酶联免疫吸附法测定血清S100A12蛋白浓度。结果:CD患者血清S100A12蛋白平均浓度为875.85(575.58～1 259.9)ng/mL,明显高于正常对照组的485.3(349.2～571.2)ng/mL(Z=-4.11,P<0.05)。结论:S100A12蛋白在CD的发病机制中起作用。血清S100A12蛋白水平与CDAI相关,可以作为疾病活动度的新指标。     

S100A6基因沉默对胰腺癌细胞侵袭的影响

目的 探讨S100A6基因沉默对胰腺癌细胞侵袭的影响和可能机制。方法 将不同浓度(3.125、6.25、12.5 nmol/L)的靶向S100A6的小干扰RNA( S100A6-siRNA)转染人胰腺癌BxPC3细胞,分别采用荧光实时定量PCR和蛋白质印迹法检测S100A6 mRNA和蛋白的表达,采用Transwell小室检测癌细胞侵袭能力,明胶酶谱法检测基质金属蛋白酶-9(MMP-9)活性。结果 S100A6-siRNA转染组细胞的S100A6 mRNA和蛋白表达呈浓度、时间依赖性明显下调,穿膜细胞数呈浓度依赖性明显减少。12.5 nmol/L的S100A6-siRNA转染组细胞转染后48 h的S100A6 mRNA表达从对照组的(100±0.3)％降到(15.3±0.2)％(P＜0.01);S100A6蛋白的表达从(83.2±0.18)％降到(13.5±0.12)％(P＜0.01);穿膜细胞数从(44.5±2.2)个降到(7.6±1.5)个(P＜0.05)。同时,S100A6-siRNA转染组细胞的MMP-9活性明显下调。结论 抑制S100A6基因表达可抑制胰腺癌细胞侵袭转移,其机制可能与下调MMP-9活性有关。     

基于免疫组化法分析肺腺癌S100A6蛋白表达与临床特征的关系

目的探讨S100A6蛋白在肺腺癌中的表达及其临床意义。方法收集2007年1月至2009年1月西安交通大学第二附属医院、第四军医大学唐都医院手术切除的肺癌标本,共计98例肺腺癌及其癌旁正常肺组织,用免疫组织化学法检标本中S100A6蛋白的表达情况,分析S100A6蛋白表达与患者临床病理特征及生存预后的关系。结果 S100A6蛋白在肺腺癌组织中的表达显著高于正常肺组织(P0.001);其表达与患者性别和年龄无相关性(P0.05),而与吸烟指数、肿瘤细胞分化、淋巴结转移、远处转移、TNM分期显著相关(P0.05);98例患者5年随访期间77例患者死亡,10例患者存活,11例患者失访,5年生存率为11.49%。其中S100A6蛋白低表达患者5年累计生存率63.6%,中位生存时间68月;中表达患者5年累计生存率14.3%,中位生存时间45月;高表达患者5年累计生存率0%,中位生存时间29月,生存曲线显示S100A6不同表达状态患者生存率比较差异有统计学意义(P0.05);COX回归模型分析显示,肿瘤分化、TNM分期和S100A6表达状态是影响肺腺癌患者预后的独立因素(P0.05);S100A6蛋白表达对肺腺癌诊断灵敏度为84.69%,特异度为69.39%。结论 S100A6蛋白在肺腺癌组织中显著过表达,与肿瘤分期、分化、转移及预后密切相关。     

Expression of S100A9 and KL-6 in common interstitial lung diseases

By evaluating S100 calcium binding protein A9 (S100A9) and Klebs von den Lungen-6 (KL-6) expression in patients with 4 common interstitial lung diseases (ILDs), we aimed to investigate whether S100A9 or KL-6 can be of any value in the differential diagnosis of these ILDs and simultaneously signal the disease progression.We collected the data of patients diagnosed with the 4 ILDs and underwent fiber-optic bronchoscopy and BAL in the First Affiliated Hospital, China Medical University from January 2012 to December 2020. The data related to BGA, C-reactive protein, pulmonary function test, total number and fraction of cells, T lymphocyte subsets in bronchoalveolar lavage fluid (BALF), and the expression of S100A9 and KL-6 in BALF and serum were collected. We analyzed, whether S100A9 or KL-6 could serve as a biomarker for differential diagnosis between the 4 common ILDs; whether the levels of S100A9 and KL-6 correlated with each other; whether they were correlated with other clinical parameters and disease severity.This study included 98 patients, 37 patients with idiopathic pulmonary fibrosis (IPF), 12 with hypersensitivity pneumonitis, 13 with connective tissue disease-associated ILD, and 36 with sarcoidosis (SAR): stage I (18), stage II (9), stage III (5), and stage IV (4). The expression of KL-6 in BALF was significantly higher in IPF patients than other 3 groups (all P-value < .05). However, there was no significant difference in the levels of S100A9 in BALF and serum between the 4 groups (P-value > .05). The levels of S100A9 in BALF of IPF patients was positively and significantly correlated with KL-6 expression and the percentage of neutrophils in BALF (P-value < .05). Along with the stage increase of SAR patients, the level of S100A9 in BALF gradually increased, which was negatively and significantly correlated with the forced vital capacity/predicted, carbon monoxide diffusing capacity/predicted%, and PaO₂ (all P-value < .05).The expression of KL-6 in BALF can be used as a biomarker to differentiate IPF from the other 3 common ILDs. While, this was not the case with expression of S100A9 in BALF and serum. However, the expression S100A9 in BALF is useful to indicate the progression of SAR. Thus, simultaneous measurement of KL-6 and S100A9 levels in BALF makes more sense in differential diagnosing of the 4 common ILDS.     

Significance of calgranulins (S100A8, S100A9 and S100A12), ferritin and toll-like receptor 4 in juvenile idiopathic arthritis children

Aim of the workTo evaluate role of calgranulins (S100A8, S100A9, and S100A12), ferritin and toll-like receptor 4 (TLR4) in juvenile idiopathic arthritis (JIA) children.Patients and methodsSera of 59 JIA Iraqi patients and 58 healthy-matched children were studied and serum levels of S100A8, S100A9, S100A12, ferritin and TLR4 assessed. Juvenile arthritis disease activity score-27 (JADAS27) was assessed.ResultsThe mean age of the patients was 10.1 ± 4.2 year; they were 40 females and 19 males with disease duration of 2.4 ± 2.6 years. The levels of S100A9 and ferritin were significantly increased in JIA patients compared to control (98 ± 63 vs. 65 ± 53 ng/ml; p = 0.004 and 57 ± 52 vs. 33 ± 31 ng/ml; p = 0.003, respectively), while S100A8, S100A12 and TLR4 levels showed no significant differences. Significant correlations were found; S100A8 with S100A9 (r = 0.27; p = 0.036) and TLR4 (r = 0.73; p = 0.001), S100A9 with TLR4 (r = 0.29; p = 0.026), and S100A12 with ferritin (r = 0.58; p = 0.001). S100A8, S100A9 and ferritin could significantly discriminate JIA from control (p = 0.035, p = 0.001, and p = 0.001, respectively). Corresponding sensitivities of S100A8, S100A9 and ferritin were 63%, 70% and 61%, and specificities were 60%, 66% and 60% at cutoff values of 28.3, 68.4 and 29.6 ng/ml, respectively. On multinomial logistic regression analysis, S100A9 and ferritin were significant predictors especially in those with positive C-reactive protein (CRP) and rheumatoid factor (RF), low JADAS27 and persistent oligoarthritis subtype.ConclusionsS100A8, S100A9 and ferritin were upregulated in sera of JIA patients. Their significance as predicting biomarkers of disease outcome was augmented, especially in CRP- and RF-seropositive, low JADAS27 and persistent oligoarticular JIA patients.     

Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF.MethodsThirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated.ResultsThe serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = −0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012).ConclusionThe serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.     

Different expression ratio of S100A8/A9 and S100A12 in acute and chronic lung diseases

Calgranulins are a family of powerful chemoattractants, which have been implicated as biomarkers in inflammatory diseases. To determine how different respiratory diseases affect the expression of calgranulins, we measured the expression of S100A8/A9 and S100A12 in bronchoalveolar lavage fluid (BALF) of acute respiratory distress syndrome (ARDS) patients and healthy volunteers by ELISA. Analysis of calgranulin expression revealed a high level of S100A12 in the lavages of patients suffering from ARDS compared to controls (p<0.001). Based on the hypothesis that the increased expression of S100A12 relative to the S100A8/A9 heterodimer was a characteristic of respiratory diseases with neutrophilic inflammation, we measured calgranulin expression in BALF of cystic fibrosis (CF) patients. Despite similarly elevated levels of S100A8/A9, S100A12 was significantly higher in ARDS compared to CF BALF (p<0.001). The differential expression of calgranulins was unique for inflammatory markers, as an array of cytokines did not differ between CF and ARDS patients. Since ARDS is an acute event and CF a chronic inflammation with acute exacerbations, we compared calgranulin expression in sputum obtained from CF and patients with chronic obstructive lung disease (COPD). Levels of S100A12 and S100A8/9 were elevated in CF sputum compared to COPD sputum, but the ratio of S100A12 to S100A8/A9 was similar in COPD and CF and reflected more closely than seen in healthy controls. The results indicate that the regulation of human calgranulin expression and the ratio of S100A8/A9 to S100A12 may provide important insights in the mechanism of respiratory inflammation.