Lipocalin-2 Test in Distinguishing Acute Lung Injury Cases from Septic Mice Without Acute Lung Injury△

doi:10.1016/S1001-9294(14)60031-6

摘要/Abstract

摘要：

Objective To explore whether the amount of lipocalin-2 in the biofluid could reflect the onset of sepsis-induced acute lung injury (ALI) in mice.Methods Lipopolysaccharide (LPS, 10 mg/kg) injection or cecal ligation and puncture (CLP) was performed to induce severe sepsis and ALI in C57 BL/6 male mice randomly divided into 5 groups (n=10 in each group): group A (intraperitoneal LPS injection), group B (intravenous LPS injection via tail vein), group C (CLP with 25% of the cecum ligated), group D (CLP with 75% of the cecum ligated), and the control group (6 sham-operation controls plus 4 saline controls). All the mice received volume resuscitation. Measurements of pulmonary morphological and functional alterations were used to identify the presence of experimental ALI. The expressions of lipocalin-2 and interleukin (IL)-6 in serum, bronchoalveolar lavage fluid (BALF), and lung tissue were quantified at both protein and mRNA levels. The overall abilities of lipocalin-2 and IL-6 tests to diagnose sepsis-induced ALI were evaluated by generating receiver operator characteristic curves (ROC) and computing area under curve (AUC).Results In both group B and group D, most of the “main features” of experimental ALI were reproduced in mice, while group A and group C showed septic syndrome without definite evidence for the presence of ALI. Compared with septic mice without ALI (group A+group C), lipocalin-2 protein expression in septic mice with ALI (group B+group D) was significantly up-regulated in BALF (P<0.01) and in serum (P<0.01), and mRNA expression boosted in lung tissues (all P<0.05). Lipocalin-2 tests performed better than IL-6 tests in recognizing sepsis-induced ALI cases, evidenced by the larger AUC of the former (BALF tests, 0.8800 versus 0.6625; serum tests, 0.8500 versus 0.7000). Using a dual cutoff system to diagnose sepsis-induced ALI, BALF lipocalin-2 test exhibited the highest positive likelihood ratio (13.000) and the lowest negative likelihood ratio (0.077) among the tests of lipocalin-2 and IL-6 in blood and BALF. A statistically significant correlation was found between lipocalin-2 concentration in BALF and that in serum (Spearman r=0.8803, P<0.0001).Conclusions Lipocalin-2 expression is significantly up-regulated in septic ALI mice compared with those without ALI. Lipocalin-2 tests with a dual cutoff system could be an effective tool in distinguishing experimental ALI cases.

关键词: lipocalin-2, acute lung injury, biomarker, sepsis, neutrophil gelatinase associated lipocalin

Abstract:

Key words: lipocalin-2, acute lung injury, biomarker, sepsis, neutrophil gelatinase associated lipocalin

Gao Zeng, Cong-wei Jia, Jie Liu, Shu-bin Guo. Lipocalin-2 Test in Distinguishing Acute Lung Injury Cases from Septic Mice Without Acute Lung Injury[J].Chinese Medical Sciences Journal, 2014, 29(2): 65-77.

参考文献 1.

1.	Mauri T, Coppadoro A, Bellani G, et al. Pentraxin 3 in acute respiratory distress syndrome: an early marker of severity. Crit Care Med 2008; 36:2302-8.
	2.He X, Han B, Bai X, et al. PTX3 as a potential biomarker of acute lung injury: supporting evidence from animal experimentation. Intensive Care Med 2010; 36:356-64.
	3.Ye SQ, Simon BA, Maloney JP, et al. Pre-B-cell colony- enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med 2005; 171:361-70.
	4.Jabaudon M, Futier E, Roszyk L, et al. Soluble form of the receptor for advanced glycation end products is a marker of acute lung injury but not of severe sepsis in critically ill patients. Crit Care Med 2011; 39:480-8.
	5.Paragas N, Qiu A, Zhang Q, et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat Med 2011; 17:216-22.
	6.Borregaard N, Cowland JB. Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. BioMetals 2006; 19:211-5.
	7.Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 1997; 45:17-23
	8.Chassaing B, Srinivasan G, Delgado MA, et al. Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS One 2012 [cited 2013 Nov 1]; 7: e44328. Availabe from: http://www. plosone.org/article/info%3Adoi%2F10.1371%2Fjournal. pone.0044328.
	9.Carlson M, Raab Y, Sevéus L, et al. Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis. Gut 2002; 50:501-6.
	10.Keatings VM, Barnes PJ. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med 1997; 155:449-53.
	11.Aigner F, Maier HT, Schwelberger HG, et al. Lipocalin-2 regulates the inflammatory response during ischemia and reperfusion of the transplanted heart. Am J Transplant 2007; 7:779-88.
	12.Roudkenar MH, Kuwahara Y, Baba T, et al. Oxidative stress induced lipocalin 2 gene expression: addressing its expression under the harmful conditions. J Radiat Res 2007; 48:39-44.
	13.André E, Stoeger T, Takenaka S, et al. Inhalation of ultrafine carbon particles triggers biphasic pro-inflammatory response in the mouse lung. Eur Respir J 2006; 28: 275-85.
	14.Connor AJ, Laskin JD, Laskin DL. Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4. Exp Mo Pathol 2012; 92:229-35.
	15.Devireddy LR, Gazin C, Zhu X, et al. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 2005; 123:1293-305.
	16.Lee S, Lee J, Kim S, et al. A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. J Immunol 2007; 179:3231-41.
	17.Xu G, Ahn J, Chang S, et al. Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation. J Biol Chem 2012; 287:4808-17.
	18.Perl M, Lomas-Neira J, Venet F, et al. Pathogenesis of indirect (secondary) acute lung injury. Expert Rev Resp Med 2011; 5:115-26.
	19.Perl M, Chung CS, Perl U, et al. Therapeutic accessibility of caspase mediated cell death as a key pathomechanism in indirect acute lung injury. Crit Care Med 2010; 38:1179-86.
	20.Sunil VR, Patel KJ, Nilsen-Hamilton M, et al. Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. Exp Mo Pathol 2007; 83:177-87.
	21.Shapiro NI, Trzeciak S, Hollander JE, et al. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Crit Care Med 2009; 37:96-104.
	22.Chakraborty S, Kaur S, Guha S, et al. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 2012; 1826:129-169.
	23.Rittirsch D, Huber-Lang MS, Flierl MA, et al. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 2009; 4:31-6.
	24.Matute-Bello G, Downey G, Moore BB, et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011; 44:725-38.
	25.Damas P, Ledoux D, Nys M, et al. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992; 215:356-62.
	26.Osuchowski MF, Connett J, Welch K, et al. Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis. Crit Care Med 2009; 37:1567-73.
	27.Remick DG, Bolgos GR, Siddiqui J, et al. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 2002; 17:463-7.
	28.Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008; 295:L379-99.
	29.Iskander KN, Craciun FL, Stepein DM, et al. Cecal ligation and punc-ture-induced murine sepsis does not cause lung injury. Crit Care Med 2013; 41:159-70.
	30.Sultan S, Pascucci M, Ahmad S, et al. Lipocalin-2 is a major acute-phase protein in a rat and mouse model of sterile abscess. Shock 2012; 37: 191-6.
	31.Luchtefeld M, Preuss C, Rühle F, et al. Gp130-dependent release of acute phase proteins is linked to the activation of innate immune signaling pathways. PLoS One 2011 May 4 [cited 2013 Nov 19]; 6: e19427. Available from: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0019427
	32.Riedemann NC, Neff TA, Guo RF, et al. Protective effects of IL-6 blockade in sepsis are linked to reduce C5a receptor expression. J Immunol 2003; 170:503-7.
	33.Mostafa Anower AKM, Shim JA, Choi B, et al. Pretreatment with interleukin-6 small interfering RNA can improve the survival rate of polymicrobial cecal ligation and puncture mice by down regulating interleukin-6 production. Eur J Pharmacol 2012; 688:76-83.
	34.Craciun FL, Schuller ER, Remick DG. Early enhanced local neutrophil recruitment in peritonitis-induced sepsis improves bacterial clearance and survival. J Immunol 2010; 185:6930-8.

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