Influence of Propofol, Isoflurane and Enflurance on Levels of Serum Interleukin-8 and Interleukin-10 in Cancer Patients

Pro-inflammatory cytokine and anti-inflammatory cytokine, maintaining a certain balance in healthy population, often expressed disorderly in cancer patients, and the surgery induced traumatic inflammation could aggravate their imbalance and disorder (Ziebell et al., 2010; Jawa et al., 2011; Marik et al., 2012). Studies have shown that anesthetic agents have certain impact on the secretion of isolated cytokine, but their effects on the expressions of isolated cytokine in vivo are still controversial (Hofstetter et al., 2005; Ward et al., 2011; Mawhinney et al., 2012). This study mainly observed the influence of propofol, isoflurane and enflurance on the expressions of interleukin-8 (IL-8) and IL-10 in cancer patients.


Introduction
Pro-inflammatory cytokine and anti-inflammatory cytokine, maintaining a certain balance in healthy population, often expressed disorderly in cancer patients, and the surgery induced traumatic inflammation could aggravate their imbalance and disorder (Ziebell et al., 2010;Jawa et al., 2011;Marik et al., 2012). Studies have shown that anesthetic agents have certain impact on the secretion of isolated cytokine, but their effects on the expressions of isolated cytokine in vivo are still controversial (Hofstetter et al., 2005;Ward et al., 2011;Mawhinney et al., 2012). This study mainly observed the influence of propofol, isoflurane and enflurance on the expressions of interleukin-8 (IL-8) and IL-10 in cancer patients.

Influence of Propofol, Isoflurane and Enflurance on Levels of Serum Interleukin-8 and Interleukin-10 in Cancer Patients
Tie-Cheng Liu pathologically at degree Ⅰ~Ⅱ according to American Society Of Anesthesiologists (ASA), and received no radio-or/and chemotherapy before the operations. All patients were randomly divided into group A (34 cases), group B (28 cases) and group C (28 cases). In group A, there were 20 males and 14 females, aged 31~65 years, with average age being (59.23±2.41) years. In group B, there were 13 males and 15 females, aged 30~65 years, with average age being (59.48±2.57) years. And in group C, there were 14 males and 14 females, aged 30~64 years, with average age being (59.53±2.39) years. Three groups are comparable as there were no significant differences in the general data , such as gender and age (P>0.05).

Methods
Anesthetic methods: 30 min before operation, intramuscular injection of 0.3 mg scopine hydrochloride and 100 mg phenobarbital sodium were routinely given, followed by induced anesthesia with induced drugs including 0.1 mg/kg midazolam, 3~5 g/kg fentanyl and 1~1.5 mg/kg succinylcholine chloride. After tracheal intubation, anesthesia machine was connected to conduct mechanical ventilation, with tidal volume, respiratory frequency and respiratory time ratio being 10 mL/ kg, 13 times/min and 1:2, respectively. Discontinuous intravenous injections of fentanyl and vecuronium bromide were performed. During the maintenance of anesthesia, 0.5~1.0 mg/kg propofol was intravenously injected to group A discontinuously, while continuous suctions of isoflurane and enflurance were subsequently performed to group B and C correspondingly, with volume fraction being 0.6%~1.0%.
Detecting methods: 3 mL venous blood was collected at each time point from all people. Kits were provided by French Immun Otech Company. The expressions of serum IL-8 and IL-10 were detected by enzyme-linked immunosorbent assay (ELLSA), with sensitivities being 31 pg/mL and 15 pg/mL respectively, which had strong specificity without cross reaction with other cytokines. The above operations were conducted strictly according to the instructions.

Observational indexes
Clinical outcomes, postoperative complications as well as the levels of serum IL-8 and IL-10 before the operation (T0), at the time of skin incision (T1), 3 h after the beginning of the operation (T2) and 24 h (T3) and 72 h (T4) after the operation were observed among 3 groups.
Statistical data analysis SPSS19.0 software was applied for all data analysis. Enumeration data was expressed by % and analyzed by X2 test, while measurement data was expressed by mean±standard deviation (x _ ±s) and analyzed by t test. Comparisons among groups were analyzed by variance analysis. P<0.05 was considered to be significantly different.

Serum IL-8 and IL-10 expression changes before and after treatment among 3 groups
The levels of serum IL-8 and IL-10 had no significant difference among 3 groups before the operation (P>0.05). After the operation, serum IL-8 and IL-10 levels increased gradually and reached the peak at T3, and were evidently higher at each time point than at T0 (P<0.01). Variance analysis indicated that at T1, serum IL-8 and IL-10 levels had no significant differences among 3 groups (P>0.05), but the level of IL-8 was obviously lower and the level of IL-10 was evidently higher at T2 and T3 in group A than     in the other 2 groups (P<0.05). However, the difference was not significant between group B and C (P>0.05). Additionally, the levels of serum IL-8 and IL-10 had significant differences among 3 groups at T4 (P<0.05). Relevance analysis suggested that the level of serum IL-8 was in positive relation with IL-10 level (r=0.952, P<0.01). As shown in Table 1 and Figures 1~3.

Correlation analysis of IL-8 and IL-10 expressions
As shown in Figure 4, the levels of serum IL-8 and IL-10 showed similar increasing and decreasing trends after operation and Pearson correlation analysis demonstrated that the level of IL-8 was in positive association with IL-10 level in all groups (r=0.952, P<0.01).

Discussion
Immunological dysfunction, which is common in cancer patients and can be aggravated by surgery-induced traumatic inflammation, becomes one of the important risk factors for cancer (Franca et al., 2013;Yu et al., 2014). With the development of molecular biology, cytokine has received more and more attentions due to its critical role in traumatic inflammatory responses. During the surgery, inflammatory mediators, like C-reactive protein, cortisol hormone and cytokines, are released in large abundance, which activate the inflammatory cells and constantly exacerbate the inflammatory responses. A researcher proposed that the balance between pro-inflammatory cytokines (IL-8 and tumor necrosis factor-α) and antiinflammatory cytokines (IL-4 and IL-10) was beneficial to eliminating the adverse impacts result from traumatic inflammatory responses and promoting the recovery of diseases (Allahtavakoli et al., 2011;de Lima et al., 2011;Sun et al., 2011;Gäbel et al., 2013;Shen et al., 2013;Verit et al., 2013;Yang et al., 2013;Zhao et al., 2013;Guo et al., 2014;Kma et al., 2014;Lu et al., 2014;Pandurangan et al., 2014;Soliman et al., 2014).
IL-8 is a kind of inflammatory cytokine produced by mononuclear macrophages and vascular endothelial cells with stronger chemotaxis. It can improve the aggregation of neutrophils on inflammatory locations and induce their degeneration and degranulation and the release of elastase. Therefore, it can produce active oxygen specis that may directly damage histocytes. Abundant researches suggested that serum IL-8 expression increased significantly during surgery of cancer patients (Tylman et al., 2011;Veenhof et al., 2011). IL-10 is an anti-inflammatory cytokine that has immune-regulating function in cellular immunity, which can inhibit monocytes from secreting pro-inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-8, and reduce major histocompatibility complex Ⅱ (MHCⅡ) on antigenpresenting cells. In addition, it can promote the release of anti-inflammatory mediators like TNF soluble receptor Ⅰand Ⅱ and IL-1 receptor antagonist, etc..
The influences of different anesthetic agents on serum cytokine expressions of surgical patients have become a hot-topic in recent researches (Schilling et al., 2011;Lisowska et al., 2013). Multiple studies found that anesthetic agents had significant influence on serum cytokines in patients who underwent surgeries (Dermitzaki et al., 2009;Reikerås et al., 2010). Propofol, as one of the anesthetic agents commonly used in clinic, has favorable sedation, anti-inflammatory responses and anti-oxidation characteristics (Cavalca et al., 2008;Gonzalez-Correa et al., 2008). A report revealed that during septicopyemia, propofol could effectively suppress the release of proinflammatory cytokines TNF-α, IL-6 and IL-8 and alleviate the lung infiltration of neutrophils and acidosis (Taniguchi et al., 2002), which was predicated to be closely associated with the action of propofol on the calcium ion (Ca+) pathway in cell membrane due to the important role of Ca+ pathway played in the cytokine secretion process. Some scholars used propofol and sevoflurane to 2 groups respectively and found that patients in sevoflurane secreted more inflammatory cytokines TNF-α, IL-6 and IL-10 and led to more severe damage on lung function, indicating that propofol could reduce the release of pro-inflammatory cytokines (Jin et al., 2013). However, Tylman (Tylman et al., 2011) et al believed that these 2 anesthetic agents had similar impact on patients' immunological responses. Baki (Baki et al., 2013) et al randomly divided 40 patients with coronary artery diseases underwent selective operations into 2 groups and treated with propofol and desflurane respectively, and the results demonstrated that serum IL-6 and IL-8 levels in propofol group were evidently higher than those in desflurane group. Inhalation anesthesia of isoflurane or enflurance is commonly used in clinic, whose effect on organic cytokine expressions has become the research focus of abundant scholars (Kumakura et al., 2013). Experimental study suggested that isoflurane might trigger cell damage by bringing about the increase of proinflammatory cytokines (TNF-α) in rats in vivo (Lin et al., 2011;Lopez-Astacio et al., 2012). Inhalation of isoflurane or enflurance under mechanical ventilation may aggravate the pro-inflammatory cytokine induced injury on human bodies by increasing the transcription of TNF-α mRNA to increase the plasma expression level. Additionally, most researchers presented that propofol could better improve the release of anti-inflammatory cytokines and inhibit pro-inflammatory cytokines than other anesthetic agents such as isoflurane and enflurance, etc. (Abdulselam et al., 2013;Erol et al., 2014;Kusku et al., 2014).
This study compared the influence of propofol, isoflurane and enflurance on the levels of serum proinflammatory cytokine IL-8 and anti-inflammatory cytokine IL-10 in cancer patients, which discovered that the levels of serum IL-8 and IL-10 showed synchronous variation trend and group A was apparently higher in the level of IL-10 but had relevantly lower ascending range of IL-8 level than other 2 groups, demonstrating that propofol had more remarkable anti-inflammatory response than isoflurane and enflurance and could better reduce the traumatic inflammatory response. Meanwhile, this study also found that the level of serum IL-10 ascended almost synchronously with IL-8 level and there was positive association, suggesting that cytokine secretion in vivo was similar to network, marked by compensatory increase of IL-10 secretion due to the ascending IL-8 level so as to maintain the balance of pro-and anti-inflammatory cytokines, which was consistent with relevant report (Lisowska et al., 2013). Though the influence of propofol on cytokines proved in this study, no unfavorable prognosis (sepsis and multiple organ failure) was observed in all patients in the following clinical observation, indicating that the selection of anesthetic agents that influenced the balance of cytokines had played no effect on immune homeostasis of human body. However, as to high risk patients who need long-term anesthetic agents for sedation or analgesia, the agents should be strictly selected in order to promote cytokines in maintaining balanced state.