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The association between blood glucose levels and matrix-metalloproteinase-9 in early severe sepsis and septic daze

  • Anja Grand. Jaehne1,
  • Namita Jayaprakashone,
  • Mark Kuzich1,
  • Violet Onkobaane,
  • Dione Blydenone &
  • Emanuel P. Rivers1

Journal of Inflammation volume xiii, Article number:13 (2016) Cite this article

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Abstruse

Groundwork

Hyperglycemia is a frequent and important metabolic derangement that accompanies severe sepsis and septic stupor. Matrix-Metalloproteinase 9 (MMP-nine) has been shown to be elevated in acute stress hyperglycemia, chronic hyperglycemia, and in patient with sepsis. The objective of this report was to examine the clinical and pathogenic link betwixt MMP-9 and blood glucose (BG) levels in patients with early astringent sepsis and septic shock.

Methods

We prospectively examined 230 patients with severe sepsis and septic daze immediately upon infirmary presentation and earlier whatever handling including insulin administration. Clinical and laboratory data were obtained forth with blood samples for the purpose of this study. Univariate tests for mean and median distribution using Spearman correlation and analysis of variance (ANOVA) were performed. A p value ≤ 0.05 was considered statistically significant.

Results

Patients were grouped based on their presenting BG level (mg/dL): BG <80 (northward = 32), 80–120 (due north = 53), 121–150 (n = 38), 151–200 (n = 23), and > 201 (northward = 84). Ascension MMP-9 levels were significantly associated with rising BG levels (p = 0.043). A corresponding increment in the prevalence of diabetes for each glucose grouping from half-dozen.3 to 54.1 % (p = 0.0001) was besides found. As MMP-9 levels increased a significantly (p < 0.001) decreases in IL-8 (pg/mL) and ICAM-1 (ng/mL) were noted.

Conclusion

This is the first written report in humans demonstrating a significant and early clan between MMP-9 and BG levels in in patients with astringent sepsis and septic stupor. Neutrophil affecting biomarkers such as IL-eight and ICAM-1 are noted to decrease as MMP-9 levels increase. Clinical chance stratification using MMP-9 levels could potentially help determine which patients would benefit from intensive versus conventional insulin therapy. In addition, antagonizing the up-regulation of MMP-ix could serve as a potential treatment option in severe sepsis or septic shock patients.

Background

Hyperglycemia is a frequent and important metabolic derangement that can occur in severe sepsis or septic shock. The upward-regulation of several hormones (glucagon, growth hormone, catecholamines, and glucocorticoids), inflammatory mediators (interleukin (IL)-1, IL-vi, Intercelluar Adhesion Molecule (ICAM-ane), and tumor necrosis gene (TNF)-alpha) accompanies the development of hyperglycemia [1, 2]. Elevated blood glucose (BG) has been associated with an increase in oxidative stress, as reflected by increment in oxygen free radical (O2 .) generation [iii]. In add-on to oxidative stress, there is also inflammatory stress, because Oii . activates a number of redox-sensitive pro-inflammatory transcription factors, such every bit nuclear factor (NF)-κB, activator poly peptide–i (AP-1), early growth response–1 (EGR-i), and hypoxia-inducible factor–α [3, 4].

Insulin administration is non only important in modulating glycemic command, but it likewise aids in antagonizing the pro-inflammatory furnishings of elevated blood glucose levels in critically illness. Insulin has been shown to suppress 3 important inflammatory mediators: ICAM–1, monocyte chemoattractant poly peptide–1 expression, and NF-κB binding in human aortic endothelial cells in vitro [3, 5, half-dozen].

Several studies attempting to elucidate the molecular mechanisms of hyperglycemia and sepsis accept revealed elevated levels of Matrix-Metalloproteinase-9 (MMP-9) [7–12]. MMP-9 is a pro-inflammatory biomarker belonging to a family of zinc-containing endoproteinases that are implicated in chronic jail cell remodeling, migration, adhesion, and apoptosis. In humans, MMPs consist of a family of approximately 26 members including the collagenases (MMP1, 8, 13), stromelysins (MMP3, 10), matrilysins (MMP7, 26), and gelatinases (MMP2, 9) [xiii, 14]. In the setting of sepsis there is a sequestration of polymorphonuclear neutrophils (PMNs) at the site of infection which is modulated through the processing of various cytokines and chemokines, in particular IL-8 and ICAM-1. MMP-9 is released past activated PMNs at the site of infection resulting in tissue injury, and further perpetuation of the vicious wheel of inflammation and tissue devastation [15].

Despite the abundance of literature in animal and human models describing the clan of elevated MMP-ix levels with two distinct entities such as hyperglycemia and sepsis, the link between BG and MMP-ix levels in humans with severe sepsis and septic shock has not been described. The aim of our study was to examine the clinical and pathogenic link between MMP-9 and BG levels in patients with early severe sepsis and septic shock.

Methods

Patients

Later on obtaining approving by the Henry Ford Health System Institutional Review Board (IRB) nosotros conducted a prospective observational study in a tertiary care, academy affiliated infirmary. Patients included in the study presented to the emergency department (ED) from 1997 to 2000 and were diagnosed with severe sepsis or septic shock. Blood samples (serum and plasma) were collected, spun, and stored at −80 °C upon presentation prior to the administration of any therapy including insulin. Patients' baseline characteristics, including basic demographics, comorbidities, presenting clinical data, and Acute Physiology and Chronic Health Evaluation Two (APACHE II) access scores were recorded. Patients were grouped by glucose levels based on recommendations in the literature for glycemic control in critical affliction during the report menstruation.

MMP-9, IL-8, & ICAM-1 immunoassays

Biomarker assays were independently performed by Biosite, Inc. (Alere), San Diego, Calif. Assays were performed using immunometric (sandwich) assays performed with NeutrAvidin-coated 384-well block microtiter plates (Pierce Biotechnology, Inc.; Rockford, Ill) and a Genesis RSP 200/8Workstation (Tecan Us, Inc., Durham, NC). Each sample was tested in indistinguishable. Before performing any assays, biotinylated primary antibody was diluted in an assay buffer containing 10 mmol/Fifty tris(hydroxymethyl)amino-methyl hydride HCl (pH 8.0), 150 mmol/50 sodium chloride, 1 mmol/L magnesium chloride, 0.1 mmol/Fifty zinc chloride, and ten mL/L polyvinyl alcohol (9Y10 kDa). The concentration of biotinylated antibody was predetermined past titration. The primary antibody (10 2 Fifty per well) was added to the plates and incubated. After washing, x g/L bovine serum albumin and 1 g/L sodium azide were added to the plate wells that were then incubated at room temperature. Next, the plates were washed three times with borate-buffered saline containing 0.02 % polyoxyethylene (20) sorbitan monolaurate (BBS-Tween).

Ten-microliter aliquots of each sample were added to each plate well, and the plates were incubated. Post-obit this incubation, the plates were washed 3 times and alkaline phosphatase-conjugated antibody (ten 2 L per well) was added to each plate well and further incubated. The concentration of the alkaline phosphatase-conjugated antibody was predetermined to ensure a linear profile in the dynamic range of interest. Afterwards additional incubation, the plates were washed nine times with Bbs-Tween. AttoPhos substrate (S1011; Promega Corporation, Madison, Wis), a fluorescence-enhancing substrate previously diluted in AttoPhos buffer (S1021; Promega), was and then added to aid in the measurement of the action of antibody-conjugated alkaline phosphatase spring in each well. The plates were then scanned in a fluorometer (Tecan Spectrafluor; Tecan U.s., Inc.) using an excitation wavelength of 430 nm and an emission wavelength of 570 nm. Each well as scanned six times at 114-second intervals, and the rate of fluorescence generation was calculated.

Statistical methods

Descriptive statistics were used to analyze comorbidities, baseline clinical data, organ dysfunction scores, and mortality. All continuous variables are expressed as mean ± standard deviation (STDE). We as well performed a univariate examination for ways and median distribution using Spearman correlation and analysis of variance (ANOVA). A p value < 0.05 was considered statistically pregnant. IBM SPSS v19.0 for Windows was used for all statistical computations.

Results

Patients

A full of 230 patients with astringent sepsis and septic stupor presenting to the ED were included in the report. Patients were grouped based on presenting BG levels equally follows: <80 mg/dL: due north = 32; 80–120 mg/dL: n = 53; 121–150 mg/dL: n = 38; 151–200 mg/dL: north = 23; >201 mg/dL: n = 84 (Tabular array. one). The age of the overall study population was 66 ± 17.2 years and the gender distribution was 53:47 (Male: Female). The mean APACHE II score of all patients was 22 ± vii. The baseline demographics for each BG group are shown in Table 1. The age, race, and gender distributions were like among the BG groupings. The rates of pre-existing atmospheric condition such equally hypertension, chronic obstructive pulmonary disease (COPD), and congestive centre failure (CHF) were similar among the BG groups. Still, in that location was an increment in the prevalence of diabetes mellitus (DM) as BG levels increased (p = 0.0001). The prevalence of DM was 6.three % (n = 2) in the low BG group (<80 mg/dL) and increased to 54.1 % (n = 46) in the high BG group (>201 mg/dL). Although non statistically significant, patients in the depression BG grouping (<80 mg/dL) and lxxx–120 mg/dL group had higher rates of pre-existing liver failure (31.3 % and 33 % respectively) when compared to other BG groups. In addition, patients in the depression BG grouping were noted to have a college incidence of pre-existing renal failure (xviii.8 %). A meaning deviation in APACHE II score on ED admission was observed between patients in the various BG groupings (p = 0.019). APACHE II scores were highest in the <80 mg/dL BG group (23.eight ± 6.nine) and in the 151–200 mg/dL group (24 ± 7.two).

Table 1 Patient basic demographics and comorbidities per Glucose Grouping

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BG levels and basic clinical data upon ED presentation

Table 2 summarizes baseline vital signs and routine laboratory findings. The mean heart charge per unit (HR), systolic blood force per unit area (SBP), and respiratory rate (RR) were similar amongst the groups. Patients with <80 mg/dL had lower body temperatures (34.8 °C ± 3.4 °C; p = 0.017) and higher fundamental venous pressures (CVP; 8.95 mmHg  ± nine.5 mmHg; p < 0.0001) when compared to the other BG groupings. The mean glucose levels (mg/dL) for each BG grouping were every bit follows: <80: 46 ± 25; 80–120: 100 ± 12; 121–150: 133 ± 8; 151–200: 173 ± 14; and >201: 543 ± 428. ANOVA revealed a statistically meaning difference in the mean BG values (P < 0.0001). Lactate levels were noted to be highest in the <80 mg/dL (x.1 mg/dL ± 5.1 mg/dL). An increment in lactate levels were noted in the subsequent BG groupings (range 5.5 mg/dL ± four.vii mg/dL to 7.3 mg/dL ± iv.2 mg/dL; p < 0.002). Consistent with the presence of infection, the >201 mg/dL BG group had the highest WBC count (16 mm3 ± eight.8 mm3), culture positivity (80 %) and bacteremia rates (42.4 %).

Tabular array 2 Patient clinical and routine laboratory findings upon presentation

Total size table

Association between BG, MMP-9, IL-eight, and ICAM-1

Figure 1 demonstrates the relationship of BG with MMP-9, IL-8, and ICAM-1 levels. Rising MMP-9 levels were significantly associated with ascent BG levels (p = 0.043). For the diverse BG (mg/dL) groupings MMP-nine levels (ng/mL) were as follows: <80: 661, 80–120: 631, 121–150: 802, 151–200: 838, and >201: 898. As MMP-9 levels increased with rising BG levels a statistically significant decrease in IL-viii and ICAM-one levels was noted (P < 0.0001). For each BG (mg/dL) group the IL-viii (pg/mL) levels were as follows: : <lxxx: 107, 80–120: 67, 121–150: 34, 151–200: 49, and >201: 31. Similarly, a significant inverse relationship was observed for ICAM-ane levels (ng/mL) for each BG group: <lxxx: 450, eighty–120: 289, 121–150: 282, 151–200: 256, and >201: 250.

Fig. 1
figure 1

Association of increasing MMP-9 (grey confined) levels with increasing claret glucose (BG) levels. Changed proportional clan of IL-8 (┈■┈) and ICAM-one (—▲—) with MMP-9 levels

Full size image

Discussion

To our knowledge this is the beginning study to establish a significant clan betwixt BG levels and MMP-9 levels in patients with severe sepsis or septic shock. In addition, we also demonstrate that every bit BG increased an inverse relationship between MMP-9 and IL-viii levels, and MMP-9 and ICAM-i levels was observed.

Currently, it is well-known that in severe sepsis and septic shock patients, hyperglycemia develops due to a combination of several factors: i) Insulin clearance is increased leading to a reduction in insulin-mediated glucose uptake; 2) Stress induced peak in plasma levels of counter-regulatory hormones, such as catecholamines, glucagon, cortisol, and growth hormone. These hormones pb to hyperglycemia due to muscle glycolysis and lipolysis, and subsequent gluconeogenesis and glycolysis in the liver; iii) Hyperlactatemia due to glycolysis in muscle caused by the counterregulatory hormones and cytokines, sometimes referred to as the "lactate shuttle" 4) Insulin resistance which could be due to a lacking GLUT4 transporter and to the deleterious effects of pro-inflammatory cytokines such every bit IL-i, IL-6, and TNF-α [16–18].

It has been demonstrated via various significant in vivo and in vitro experimental studies that in the setting of acute or chronic hyperglycemia (diabetes mellitus), glucose can induce the increase of pro-inflammatory transcription factors such equally NF-kB, AP-one, and EGR-ane. The MMP-9 promoter region has been described to contain responsive elements to the aforementioned transcription factors and thus up-regulating MMP-9 transcription and activity [5, ten, 19, xx]. Our results may suggest a possible up-regulation of MMP-9 in the setting of both acute and chronic hyperglycemia. The majority of patients with BG ranging from 121 mg/dL to 200 mg/dL had increased MMP-nine levels most likely secondary to an acute increase in their BG levels in the setting of disquisitional disease. This is inferred from the study data as the prevalence of DM in patients with a BG ranging from 121 mg/dL to 200 mg/dL was only five % to 17 %. Consistent with the literature, the highest MMP-9 level (898 ng/mL) was noted in patients in the high BG (>201 mg/dL) group. This grouping had the highest mean BG level (543 mg/dL ± 428 mg/dL) upon presentation to the ED and information technology as well had the highest prevalence of DM (56 %).

Loftier MMP-ix levels have been identified in patients in severe sepsis or septic shock. In addition to the upwards-regulation of MMP-9 gene transcription secondary to pro-inflammatory factors, MMP-9 levels are increased in the setting of sepsis due to the release of MMP-nine by activated PMNs at the site of infection causing tissue injury and further perpetuating the vicious cycle of inflammation and tissue destruction [15, 21]. The significant ascension of MMP-9 across the BG groupings in this study cannot solely be attributed to acute (stress) or chronic hyperglycemia. In our report patients with low BG (<80 mg/dL) or normoglycemia (eighty–120 mg/dL) still had elevated MMP-9 levels (661 ng/mL and 631 ng/mL respectively) leading us to the decision that the MMP-9 top in these two groups is probably due to the increase in neutrophil activation rather than stress response or chronic hyperglycemia [22].

The rise in MMP-9 levels in patients with severe sepsis or septic daze has been described to occur very early on in the disease procedure. In an experimental study involving human being subjects Albert et al., demonstrated that MMP-9 levels peaked 2 h after the administration of bacterial lipopolysaccharide (LPS) [23]. Nakamura et al., provided the first written report of elevated plasma MMP-9 levels in twenty patients with septic shock. They were able to demonstrate that plasma MMP-9 concentrations were significantly higher in the non-surviving patients with septic daze than in the surviving patients with septic shock [24]. Since then, various studies have corroborated the increment of MMP-9 levels in patients with severe sepsis or septic shock and their poor outcomes [11, 12, 25–27]. In i of our previous study in which we described the natural history of circulatory biomarker activity in the most proximal phases of severe sepsis and septic shock we also noted that MMP-ix levels peaked early (6 h) after presentation [28].

The ascent of MMP-ix in septic patients can be due to: 1) genetic up-regulation and ii) release by activated neutrophils. Together with MMP-nine levels we measured the levels of two biomarkers (IL-8 and ICAM-1) intimately involved with neutrophil function. IL-viii, a member of the CXC chemokine family has been reported to be elevated and play a function in the pathophysiology of sepsis because of its ability to attract, activate and degranulate neutrophils [29, 30]. In addition, the expression of ICAM-i (a jail cell surface glycoprotein) is increased on the prison cell surface of neutrophils assuasive it to attach and drift through the endothelium during sepsis [31, 32]. Our results demonstrate the existence of an changed relationship between MMP-9 and IL-8 as well equally MMP-9 and ICAM-1 equally BG levels increased. A possibility backside the changed relationship noted between MMP-nine and IL-viii is that MMP-9 is known to cleave a specific site of IL-viii molecular structure rendering a variant IL-8 molecule which is 10 to xxx fold more potent in neutrophil activation [33, 34]. We theorize that our assay provided us with the measurement of the native IL-eight molecule and not the variant IL-8 form which we conceptually believe to be elevated. The same observation describes the relationship betwixt IL-8 and MMP-nine from a proteonomic and metabolomic point of view. However, the possibilities of genomic links between IL-eight and MMP-ix needs to be further investigated. To explain the relationship between ICAM-1 and MMP-ix is more challenging as in that location is a scarcity of studies describing this relationship. In the field of oncology MMP-nine has been shown to proteolytically cleave the extracellular domain of ICAM-1 leading to its release from the cell surface [35]. Thus, it would lead us to believe that ICAM-1 levels should in fact rise every bit MMP-9 levels increase. Our observation contrast this finding. A possible explanation to the rise of MMP-nine and decrease of ICAM-ane levels may be due to the direct effect of insulin on such biomarkers. Aljada et al., demonstrated that insulin inhibits the expression of ICAM-ane in human aortic endothelial cells mediated by an increment in nitric oxide (NO) release and nitric oxide synthase (NOS) expression [36]. On the other paw, Fischoeder et al., described that insulin was a potent inducer of MMP-ix activity in main homo monocytes [37].

The early pathogenic link between elevated MMP-nine levels and elevated BG levels brand it plausible to consider that early inhibition or removal of this biomarker may have therapeutic potential. Antibiotics, such as the tetracyclines inhibit MMPs, not only by chelating the zinc and calcium ions just besides past affecting the induction of the MMP genes. The therapeutic assistants of tetracyclines over prolonged periods of time may cause undesirable side effects, such as gastrointestinal disturbances and emergence of antibiotic resistance. A contempo pilot study reported a low side effect profile of doxycycline (tetracycline) based on sub-antimicrobial concentrations dosing (100 mg intravenous (IV) daily, followed by 50 mg Four once daily for two days). Notwithstanding, their results showed no effect on MMP-9 levels [38]. The chemically modified tetracyclines (CMT), which lack antibacterial activity only retain the associated anti-inflammatory backdrop of tetracyclines are the preferred MMP inhibitor because they offer several advantages over conventional tetracyclines. The CMT accept been proposed to induce no gastrointestinal side furnishings or toxicities, attain higher concentrations in plasma, and cantankerous the blood–brain barrier and blood-retina barrier [39]. In an animal model for sepsis, Maitra et al., demonstrated that MMP-9 levels together with glutamic oxaloacetic acid transaminase (GOT), glutamic pyruvic transaminase (GPT), and nitric oxide (NO) were decreased when septic rats were pre-treated with CMT 24 h and i h prior to cecal ligation and puncture (CLP) [40]. They also reported that the 24 h mortality rates for CLP rats were much higher in the untreated group (30 %) when compared to the CMT pretreatment group in which no deaths were reported. In this case, the safe assistants of CMT in the setting of sepsis has shown to effectively subtract MMP-nine levels and improve survival. However, the more clinical relevant question is to decide the advisable handling window in which CMTs tin be administered in order to decrease MMP-9 levels, improve survival, and subtract the sequela of sepsis (i.due east. ARDS; liver failure). Halter et al., performed an animal study to test the hypothesis of a handling window during which CMT could exist administered in the setting of sepsis. Fifty-fifty though they did not specifically measure MMP-nine levels, they discovered that CMT given at 6 and 12 h afterwards CLP improved survival and lung injury rates when compared to the group that received CMT at 24 h. Therefore, Halter's group concluded that CMT tin be administered as late as 12 h afterward septic insult [41].

Some other alternative that has shown to decrease circulating levels of MMP-9 and improve survival in the setting of sepsis is the use of hemoperfusion using polymixin B immobilized on fibers (PMX-F). Nakamura et al., demonstrated that hemoadsorption therapy using PMX-F columns decreased the level of circulating MMP-9 and improved the survival rate of the patients with septic shock. They hypothesized that hemoperfusion therapy with PMX-F attenuated the increase in plasma MMP-9 concentrations in patients with septic shock by reducing plasma endotoxin [24].

Much controversy has been generated in regards to glycemic command since the landmark commodity of van den Berghe et al., which demonstrated decreased mortality in critically ill patients treated with intensive insulin therapy [42]. Since then, several RCTs and meta-analyses have emerged revealing no mortality benefits in critically ill patients initiated on an intensive insulin therapy [43–48]. In fact, the NICE-SUGAR trial demonstrated an increase in mortality in patients undergoing intensive glucose control (BG level target ≤ 110 mg/dL) when compared to the group treated with a BG target of 180 mg/dL [49]. In order to reach adequate BG control in septic patients a different arroyo may need to exist undertaken. This report shows a close association between elevated pro-inflammatory cytokines and the evolution of hyperglycemia in astringent sepsis and septic shock patients. Therefore, adjusting treatment based on the level of pro-inflammatory cytokines may exist an selection for adequate glucose control [l, 51]. Nakamura et al., demonstrated a significant positive correlation between a pro-inflammatory cytokine (IL-6) and BG level in septic patients. Their results showed that the rate of successful glucose control decreased with an increase in the claret IL-vi level and that in the failed glucose command group the insulin dose per 100 kcal energy intake was college [51]. Keeping in mind the concept of hypercytokinemia and hyperglycemia in septic patients together with the results reported by Fischoeder et al., in which insulin was establish to be a potent inducer of MMP-9 activity in primary human monocytes [37], nosotros hypothesize that MMP-ix levels may serve as a marker to help stratify septic patients to an intensive versus conventional insulin therapy grouping. Nosotros believe that patients with elevated MMP-9 and BG levels may exist stratified to a conventional insulin therapy group (BG target of 180 mg/dL) and insulin should exist judiciously used to avoid farther release of MMP-9 every bit this will subsequently increase the rate of extracellular matrix (ECM) remodeling and its sequelae.

Notable strengths of this report include the large number of patients recruited and the ability to mensurate MMP-9 levels very early in the disease process. The MMP-ix levels were measured upon presentation to our ED earlier any treatment (i.eastward. antibiotics, intravenous fluids, or insulin) was initiated. Together with the conventional therapeutic strategies used for septic patients, antagonizing the up-regulation of MMP-9 could serve equally a potential treatment option. In order to constitute the employ of MMP-9 as a possible biomarker for glucose control and likewise as a therapeutic target in septic patients farther prospective trials are required. In addition, more studies are likewise required to explain the changed relationship noted betwixt IL-8 and ICAM-1 with MMP-9.

Conclusion

This prospective observational study in humans demonstrates a significant and early on association between MMP-9 and BG levels in patients with severe sepsis and septic stupor. Neutrophil affecting biomarkers such equally IL-8 and ICAM-1 are noted to decrease as MMP-9 levels increase. Run a risk stratification using MMP-9 levels could potentially aid determine which patients would benefit from intensive versus conventional insulin therapy. In addition, antagonizing the upwardly-regulation of MMP-ix could serve every bit a potential treatment option in astringent sepsis or septic shock patients.

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  1. Henry Ford Hospital, 2799 Due west Chiliad Blvd, Detroit, MI, 48202, USA

    Gul R. Sachwani, Anja One thousand. Jaehne, Namita Jayaprakash, Marker Kuzich, Violet Onkoba, Dione Blyden & Emanuel P. Rivers

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Correspondence to Gul R. Sachwani.

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The authors declare that they accept no competing interests.

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ER and AK provided substantial contributions to the conception and pattern, acquisition of data, analysis, and estimation of information. GS provided estimation of data, drafted the article, and revised information technology critically for of import intellectual content. NJ provided collection of data. All contributing authors (ER, AK, NJ, MK, VO, and DB) provided regular revisions and feedback for the final manuscript. All authors read and approved the final manuscript.

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Sachwani, K.R., Jaehne, A.K., Jayaprakash, N. et al. The clan between blood glucose levels and matrix-metalloproteinase-9 in early severe sepsis and septic shock. J Inflamm xiii, xiii (2016). https://doi.org/10.1186/s12950-016-0122-7

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Keywords

  • Matrix-Metalloproteinase-9
  • MMP-9
  • Septic shock
  • Sepsis
  • Cytokines
  • IL-8
  • ICAM-1
  • Glucose

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