trem-1 ( triggering receptor expressed on myeloid cells ) , first described in 2000 , belongs to a family related to the natural killer cell receptors and is constitutively expressed on the surface of myeloid cells neutrophils , monocytes , and macrophages . although the biochemical structure of trem-1 ligands remains to be identified , some studies suggest for inflammatory response products participation . expression of trem-1 is upregulated after stimulation with bacterial and fungal products , and also sterile noninfectious stimuli  inflammatory cytokines or other mediators of inflammation , for example , prostaglandin e2 ( pge2 ) and some endogenous substances released during inflammation  damage - associated molecular patterns [ 26 ] . hmgb1 ( high mobility group box 1 protein ) and hsp70 ( heat shock protein ) released from necrotic cells function as endogenous danger signals , and trem-1is involved in mediating proinflammatory responses . other results   provide evidence thattrem-1may contribute the development of nonmicrobial inflammatory diseases through the enhancement of inflammatory responses . hypoxia itself modulates the gene expression profile in human mature dendritic cells , and trem-1 molecule was defined as a novel hypoxic marker in vitro and in vivo . the involvement of trem-1 activation in the enhancement of inflammatory response mediated by toll - like receptor-2 and -4 stimulation was detected . myeloid cells activation upon a ligand binding to this receptor generally results in inflammatory response amplification , enhanced production of proinflammatory mediators , mainly of tumour necrosis factor - alfa ( tnf- and of interleukin-8 ( il-8 ) [ 2 , 10 ] , increased expression of costimulatory molecules on the surface of macrophages , and enhanced antigen presentation that triggers t - cell proliferation [ 1 , 10 ] . neutrophils activated through trem-1 enhance their respiratory burst activity , degranulation , phagocytosis , release of myeloperoxidase , and il-8 , respectively . trem-1 by propagating inflammatory responses in inflammatory diseases thus accelerates not only the immune system activation , but also tissue destruction . however , anti - inflammatory cytokines synergistically inhibit its expression [ 10 , 12 ] . the membrane form of trem-1 can be cleaved from the surface of activated myelocytes by plasma metalloproteinases and its ectodomain is released into microenvironment . this soluble trem-1 molecule ( strem-1 ) could act as adownregulator of inflammation  binding to the natural ligand , strem-1 prevents its binding to the membrane trem-1 and subsequent cell activation . strem-1 can be measured in biological fluids and may be useful as a diagnostic tool . the highest levels of strem-1 molecules have been found in patients with sepsis   and other inflammatory diseases caused mainly by extracellular microorganisms  bacteria and fungi [ 1518 ] , as well as inflammatory states of noninfectious origin , for example , rheumatoid arthritis [ 19 , 20 ] . knowledge thatasthmais an inflammatory disorder   has prompted us to investigate the plasma levels of strem-1 in patients suffering from allergic asthma bronchiale . 76 patients suffering from asthma bronchiale ( ab ) ( 32 men , 44 woman ) , mean age = 37.4  21.4 ) were enrolled in our study . 28 out of them suffered from a mild intermittent ab , 18 from a mild persistent ab , 14 from a moderate persistent ab , and 16 from a severe persistent ab . inclusion criteria for asthma stage classification were according the global initiative for asthma ( gina ) guidelines . out of all ab patients , 25 patients were in acute exacerbation ( eab ) , the rest of them ( 51 ) were without acute exacerbation ( non - exacerbated ab - neab ) . 30 ab patients suffered from respiratory tract obstruction , 46 were without respiratory tract obstruction . all patients were treated with corticosteroids , 11 patients with severe persistent ab were on anti - ige monoclonal antibody ( omalizumab ) therapy . patients originated from specialized allergo - immunological outpatients ' departments . exacerbated ab patients with moderate persistent and severe persistent ab were in the care of institute of pneumology and phthisiology , comenius university , university hospital in bratislava . all patients were carefully examined by their physicians , they underwent spirometric examinations , bronchoprovocation test , allergen skin tests , and levels of total ige were detected too . height and body mass of patients the presence of airway obstruction was defined according to criteria of the european respiratory society , when the ratio of forced expiratory volume in one second ( fev1 ) to vital capacity ( vc ) , ( fev1/vc ) , was less than 88% of the reference value in men and less than 89% of the reference value in women . degrees of obstructive ventilatory disorders were defined according to the decrease of fev1 ( forced expiratory volume in one second ) as follows : mild degree ( mild obstructive ventilatory disorder ) : 60% of the reference value lower limit of normal , moderate degree ( moderate obstructive ventilatory disorder ) : 59%45% of the reference value , and severe degree ( severe obstructive ventilatory disorder ) : less than 45% of the reference value . however , medical reports with diagnostic conclusions of these tests , that is , asthma bronchiale with mild , moderate , or severe degree of obstructive ventilatory disorder , respectively , were available for each patients . one group represented patients without obstructive ventilatory disorder , the second included patients with mild , moderate , and severe obstructive ventilatory disorder . so , in statistic evaluation , the presence of bronchoconstriction was defined as nominal variable ( 0-without bronchoconstriction , 1-with bronchoconstriction ) . the bronchial hyperreactivity ( hyperresponsiveness ) was considered when fev1 fell by 20% after metacholine dose of 8 mg / ml ( pc20 < 8  mg / ml ) . the study was approved by the local ethical committee of faculty of medicine comenius university in bratislava and written informed consent was obtained from all patients . the total plasma ige level was determined in all patients by an electrochemiluminescence method ( modular analytics e170 , roche , usa ) . patients were assessed for both total and differential blood cell counts ( total numbers of leucocytes , red blood cells , platelets , absolute , and relative number of neutrophils , lymphocytes , monocytes , eosinophils , and basophils by an optic flow cytometry ( sysmex xt 1800i ( sysmex corporation ) . plasma levels of crp ( c - reactive protein ) were detected turbidimetrically ( advia 2400 , siemens ) directly at the day of blood collection . the control group of healthy subjects represented 39 volunteers ( 21 men , 18 woman ; mean age  std = 37.3  13.7 ) . none of these subjects suffered from ab and all of them were without any history of pollen allergy . plasma levels of strem-1 were investigated by a sandwich elisa test ( human strem-1 elisa ; r&d , quantikine , minneapolis , usa ) , exactly according to instructions of the manufacturer . the one - sample kolmogorov - smirnov test was used to determine whether the investigated population followed a normal distribution . either anova or nonparametric mann - whitney u - test were used to determine the difference and the statistical significance . the association of strem-1 plasma levels with clinical stage of ab was evaluated by kruskal wallis test . for correlation analysis of non - parametric continuals and nominal variables roc curve analysis was used to determine the specificity and sensitivity of strem-1 test . for multiple comparison , the bonferonni correction was used and only a p value < 0.005 was considered statistically significant . the group of ab patients was divided into the mild intermittent ab , the mild persistent ab , the moderate persistent ab , and the severe persistent ab subgroups . when we analysed age of patients in the particular subgroups , we found asignificant correlation between the age and severity of the disease ( table 1 ) . the rest of results are listed as median and interquartile range ( iqr ) . statistically highly significantly elevated plasma levels of strem-1 in ab patients were observed ( 92.3 pg / ml  125.6 ) compared to those in healthy subjects without ab and any pollen allergy ( 25.7  pg / ml  9.2 ; p = 0.0001 , table 2 , figure 1 ) . kruskal - wallis test revealed asignificant association between the plasma levels of strem-1 and clinical stages of ab ( p < 0.005 ) . plasma levels of strem-1 were statistically significantly higher in moderate and severe ab patients comparing to mild intermittent ab patients . statistically significantly higher plasma levels of strem-1 were found in exacerbating ab patients ( eab ) compared to those without ab exacerbation ( neab ) : eab = 170.5  78.2  pg / ml ; neab = 59.1  pg / ml  78.2  pg / ml ; p = 0.0001 , table 2 ) . the eab patients experienced also higher numbers of leukocytes ( p = 0.014 ) and absolute number of neutrophils ( p = 0.014 , table 3 ) . however , the relative number of eosinophils were statistically significantly higher in nonexacerbating ab patients ( p = 0.045 ) . both , the absolute and relative number of monocytes and lymphocytes were lower in the eab patients , however , these differences did not reach statistical significance . comparing plasma levels of strem-1 in the group of ab patients suffering from respiratory tract obstruction ( rto ) with those in the rto negative group ( rto ) , statistically significant differences were observed ( rto = 176.4  pg / ml  177.8 ; rto= 52.0  pg / ml  64.0 ; p < 0,0001 , table 2 ) . patients with respiratory tract obstruction had also higher plasma levels of crp ( p = 0.027 ) and plasma levels of strem-1 calculated per one myelocyte ( i.e. , neutrophil and monocyte , p = 0.011 ) than those without respiratory tract obstruction ( table 4 ) . spearman 's correlation test ( table 5 ) showed that plasma levels of strem-1 significantly correlated with the clinical stage of ab ( p = 0.0001 ) , the degree of respiratory tract obstruction ( p = 0.0001 ) , and the presence of anti - ige omalizumab therapy ( p = 0.0001 ) . the plasma levels of strem-1 in ab patients also significantly correlated with the number of leukocytes ( p = 0.002 ) and the absolute number of neutrophils ( p = 0.001 ) . the correlation of strem-1 with increased number of neutrophils belong to rather notable findings . eventually , the levels of strem-1 significantly correlated with those calculated for one myelocyte ( p = 0.0001 ) . the sensitivity and specificity for strem-1 concentrations the asymptomatic lower bound confidence interval for this test was 0.78 and upper bound confidence interval 0.93 . asthma 's main features include chronic airways inflammation with a variable degree of air - flow obstruction and bronchial hyperresponsiveness , leading to paroxysmal symptoms of wheeze , cough , shortness of breath , and chest tightness . antigen - specific th2 cells and their cytokines il-4 , il-5 , and il-13 orchestrate the allergic inflammation in asthmatic patients [ 2729 ] . th17 cells and il-23 are also involved in antigen - induced airway inflammation , granulopoiesis activation , and neutrophil recruitment mainly in severe asthma , of which neutrophil infiltration is one of the hallmarks [ 3033 ] . in our study , we investigated the plasma levels of a new inflammatory marker strem-1 in pollen allergy ab patients . our results revealed more than 3.5 times higher levels of strem-1 in patients with ab compared with healthy subjects without ab and without history of pollen allergy ( p = 0.0001 ) , indicating for the presence of inflammatory process in asthma patients . the elevated levels of plasma strem-1 significantly correlated with clinical stage and severity of ab ( table 2 , figure 1 ) . the highest levels of strem-1 were found in patients with moderate and severe persistent ab . the association of the clinical stage of ab patients with their age is documented in table 1 . we found also significantly higher levels of strem-1 in ab patients in exacerbation ( eab ) compared with non - exacerbating ab patients ( p < 0.0001 ) . the group of eab patients had also significantly higher number of leukocytes ( p = 0.014 ) and neutrophils ( p = 0.014 ) than neab group of patients ( table 3 ) . respiratory tract obstruction was also followed by elevated levels of strem-1 ( p < 0.0001 , table 2 ) , crp ( p = 0.027 ) , leukocytes ( p = 0.013 ) , and absolute number of neutrophils ( p = 0.008 , table 4 ) . investigations of plasma levels of strem-1 in all subjects of atopic ab patients disclosed the statistically significant correlation of its levels with the clinical stage of ab , respiratory tract obstruction , levels of crp , the presence of anti - ige therapy , number of leukocytes , absolute number of neutrophils , and the level of strem-1 calculated per one myelocyte , respectively ( table 5 ) . there are two papers in pubmed concerning the role of membrane trem-1 in ab [ 16 , 34 ] , however , the levels of strem-1 in ab patients have not been studied yet , so we can not compare our results . elevated levels of strem-1 accompanied by increased number of neutrophils in exacerbated asthma bronchiale ( table 3 ) , asthma with respiratory tract obstruction ( table 4 ) , and severe forms of asthma ( table 5 ) in our group of atopic ab patients support the results and the opinion of the authors that point to an important role of neutrophils in asthma [ 27 , 32 , 33 ] . although eosinophilic airway inflammation is recognized as an important feature of some patients with chronic stable asthma , neutrophils are the first cells recruited to the site of the allergic reaction and are eliminated by apoptosis during the resolution of the allergic response . our findings of increased number of eosinophils in ab patients without acute exacerbation supports this fact ( table 3 ) . the presence of neutrophils may influence clinical presentation and has been linked to the development of severe chronic asthma and sudden severe attacks . our results support this knowledge , increased number of neutrophils that we found in severe forms of asthma underlies this opinion . moreover , as strem-1 is cleaved and released from the surfaces of activated neutrophils and monocytes , elevated plasma levels of strem-1 also underline the role of neutrophils in inflammation that accompaines these clinical conditions . our results show that the plasma levels of strem-1 are highly elevated in severe forms of asthma , reflect the clinical stage of ab , state of exacerbation , respiratory tract obstruction , and correlate with the number of leukocytes , mainly neutrophils . these results point to the role of neutrophils in inflammation that accompanies these clinical conditions . our results highlight the potential usefulness of the assessment of the soluble form of trem-1 in plasma of ab patients .
the knowledge that asthma is an inflammatory disorder has prompted us to investigate the plasma levels of a new inflammatory marker strem-1 that is released from the surfaces of activated neutrophils and monocytes . 
 the plasma levels of strem-1 were analysed by a sandwich elisa test in the cohort of 76 patients with allergic asthma bronchiale and 39 healthy controls . 
 our results revealed more than 3.5 times higher levels of strem-1 in ab patients ( 92.3  pg / ml    125.6 ) compared with healthy subjects ( 25.7  pg / ml    9.2 ; p = 0.0001 ) . 
 higher levels of strem-1 were found also in patients with exacerbated ab ( 170.5  pg / ml    78.2 ) compared with nonexacerbated ab patients ( 59.1    78.2 ; p < 0.0001 ) , patients with respiratory tract obstruction ( 176.4  pg / ml    177.8 ) , than those without obstruction ( 51.99  pg / ml   64.0 ; p < 0.0001 ) and patients with anti - ige therapy ( p < 0.0001 ) 
 . levels of strem-1 correlated with number of leucocytes ( p = 0.002 ) , and absolute number of neutrophils ( p = 0.001 ) . elevated plasma levels of strem-1 reflect the severity , state of exacerbation , presence of respiratory tract obstruction in ab patients and together with increased number of neutrophils point to the role of neutrophils in inflammation accompanying ab .