**2. The short overview of the immune system and stress response to a surgery**

The surgery-associated tissue damage leads to the activation of the immune system and the inflammatory response. The bidirectional *r*elationship between the neuroendocrine and

The Stress Response and Its Functional Implications in the Immune

the components of the humoral response.

molecules included MHC.

al., 1997).

Response After Surgery in Patients with Chronic Inflammation Undergoing Arthroplasty 17

**lymphocytes/ plasma cells** is the synthesis and the secretion of antibodies associated with

**Immunoglobulins (antibodies**) are formed by - two identical light (L) and the two identical heavy (H) chains. The main form of the immunoglobulins are described: one of them is presented on the membrane surface of the B cells as the antigen specific receptor (BCR). However, the other one exists as the soluble form and is produced by plasma cells. The biologic results of the antigen-antibody reactions include many consequences such as agglutination with soluble antigen, as well as precipitations and activation of complement

The activation of the B cells starts through the B cell receptor ( BCR) at the cell membrane and triggers the intracellular signaling pathways regulating the transcription of antibodies and cytokines genes (Coico & Sunshine 2009). The BCR has the exceptional ability to react with many different types of antigens such as peptides DNA, lipids and carbohydrates. **The T lymphocytes** are a part of the **cell-mediated** immunity and their role is the cytokines production and support of the B cells activation. The T lymphocytes are divided into following subsets: h*elper (Th), cytotoxic (CCTL), regulatory (T reg) and memory (Tm).*  Similarly B cells and the T cells also have the antigen binding receptor on their surface (TCR) but in contrast to the BCR, the TCR interacts with small fragments of antigenic proteins called peptides which are presented on APC in association with class I and class II

**The major histocompatibility complex (MHC)** in the humans called human leukocyte antigen (HLA) has many different diverse immunological and non-immunological functions. The MHC is divided into two types of molecules encoded by the MHC classes: MHC class I and MHC class II. Both of them are recognized by different subsets of the T cells.The MHC class I molecules have the crucial task of the presentation of an antigenic protein to the T Cytotoxic lymphocytes (CD8+) while MHC class II presents an antigen to T Helper lymphocytes (CD4+). Molecules of MHC class I are found on the surface of all nucleated cells of human body while molecules of MHC class II are found on the surface of the APC *(*Coico & Sunshine 2009*).* The MHC complex includes the most polymorphic genomes in the human genomes with many consequences related to the transplantation and the autoimmune disease. It turned out that the human leukocyte antigen HLA-B27 is tightly correlated with the frequency of the spondylarthritis (Cauli et al., 2002; Jin & Wang, 2003). The adhesion molecules CD4+ and CD8+ are necessary to enhance the binding of the T cells and the APC. The expression of CD4+ and CD8+ is variable on the T cells. The normal ratio

**The dendritic cells (DC)** are classical, the most potent APC and by this way they contribute to connection between the innate and acquire immune systems. The dendritic cells present the ability to initiate several immune responses such as stimulation of T and B lymphocytes and the resistance against various infections and cancer cells (Bodey et

**Cytokines** are produced by all cells of the human immune system. Cytokines form a complex network secretory molecules which exert their effects on the phases of the immune response. Cytokines are immensely responsible for the transduction of information among the immune system cells and are the very important components of the bi-directional communication between the immune and the neuroendocrine systems (Lisowska et al., 2008). Depending on the prevailing effects of inflammatory response they are called as a pro-inflammatory or anti-inflammatory. The pro-inflammatory cytokines are mainly

of CD4+ T cell to CD8+ T cells is approximately 2:1 in healthy population.

that results in the neutralization of bacterial toxins and microorganisms activity.

immune systems with the participation of common mediators seems be essential for the mechanisms of the chronic inflammatory state including hormonal and immune changes. The tight coexistence the autonomic nervous system and the hypothalamic-pituitary adrenal axis (HPA axis) is extremely important for damping as well as hastening the reaction of the immune system. The presence of the chronic inflammatory state is exactly with the dysfunction of the neuroendocrine-immune system. The crucial aims of the immune system are the organism protection by recognition and elimination of the antigens which are usually different various components but generally are infectious agents such as bacteria, viruses and fungi.

Two types of immunity can be distinguished from the immune system: the nonspecific (innate) and the specific (acquired) response. There are two forms of acquired response the humoral and the cell mediated.

### **2.1 The innate immunity**

The innate immunity contains the following elements such as: the Langerhans cells inside the skin, the submucosal tissues of the respiratory and alimentary tracts, the complement system, the phagocytic cells (granulocytes and macrophages) and the glial cells. Lymphocytes, granulocytes and macrophages are responsible for the elimination of antigens. The initiation of the immune response has its own essential origin in the mononuclear phagocyte system (MPS) which is represented by monocytes and macrophages (both type of cells accumulate in the site of surgery). During the first step of immune response the antigen is absorbed by MPS cells and degraded into peptides in the intracellular compartments. The pathogen-associated molecular patterns (PAMPs) are the molecules associated with microorganisms which can be recognized by sophisticated presentation to the pattern-recognition receptors (PRR) and the Toll-like receptors (TLRs) situated on the membrane surface or inside of various cells. They have unique ability of the triggering innate immune responses. Toll like receptors (TLR ) belong to the PRR family and play key role whilst the induction of the immune response. The TLRs are also expressed by immune cells and various other cells such as endothelium, muscle cells and adipocytes. It can be said they participate while both types of immune response especially during the induction and the regulation of T and B lymphocytes activates (Majewska & Szczepanik 2006).

### **2.2 The cells and mechanism of the acquired immunity**

When the innate mechanisms are not enough to inactive microorganisms then the proteins from pathogenic antigens are presented to molecules expressed on B or T cells becoming their activators. The process called the antigen processing and the presentation leads to the proliferation of the activated lymphocytes and is typical for the acquired immunity.

As the after-consequence of the response to signals from the mononuclear phagocytes the B lymphocytes differentiate into plasma cells. Moreover, T lymphocytes become active and starts to release soluble factors known as cytokines (Stevenson et al., 1990).

Contrasted with innate **the acquired response** is more sophisticated form of the immunity and requires longer activation period. The main cells of the **acquired immunity** are both type of lymphocytes and also the antigen presenting cells (APC) such as dendritic cell. Chronic inflammatory state can modify these elements and delay the triggering of the both mechanism of the immune response. The primary role of the **B** 

immune systems with the participation of common mediators seems be essential for the mechanisms of the chronic inflammatory state including hormonal and immune changes. The tight coexistence the autonomic nervous system and the hypothalamic-pituitary adrenal axis (HPA axis) is extremely important for damping as well as hastening the reaction of the immune system. The presence of the chronic inflammatory state is exactly with the dysfunction of the neuroendocrine-immune system. The crucial aims of the immune system are the organism protection by recognition and elimination of the antigens which are usually different various components but generally are infectious agents such as bacteria,

Two types of immunity can be distinguished from the immune system: the nonspecific (innate) and the specific (acquired) response. There are two forms of acquired response the

The innate immunity contains the following elements such as: the Langerhans cells inside the skin, the submucosal tissues of the respiratory and alimentary tracts, the complement system, the phagocytic cells (granulocytes and macrophages) and the glial cells. Lymphocytes, granulocytes and macrophages are responsible for the elimination of antigens. The initiation of the immune response has its own essential origin in the mononuclear phagocyte system (MPS) which is represented by monocytes and macrophages (both type of cells accumulate in the site of surgery). During the first step of immune response the antigen is absorbed by MPS cells and degraded into peptides in the intracellular compartments. The pathogen-associated molecular patterns (PAMPs) are the molecules associated with microorganisms which can be recognized by sophisticated presentation to the pattern-recognition receptors (PRR) and the Toll-like receptors (TLRs) situated on the membrane surface or inside of various cells. They have unique ability of the triggering innate immune responses. Toll like receptors (TLR ) belong to the PRR family and play key role whilst the induction of the immune response. The TLRs are also expressed by immune cells and various other cells such as endothelium, muscle cells and adipocytes. It can be said they participate while both types of immune response especially during the induction and the regulation of T and B lymphocytes activates (Majewska &

When the innate mechanisms are not enough to inactive microorganisms then the proteins from pathogenic antigens are presented to molecules expressed on B or T cells becoming their activators. The process called the antigen processing and the presentation leads to the

As the after-consequence of the response to signals from the mononuclear phagocytes the B lymphocytes differentiate into plasma cells. Moreover, T lymphocytes become active and

Contrasted with innate **the acquired response** is more sophisticated form of the immunity and requires longer activation period. The main cells of the **acquired immunity** are both type of lymphocytes and also the antigen presenting cells (APC) such as dendritic cell. Chronic inflammatory state can modify these elements and delay the triggering of the both mechanism of the immune response. The primary role of the **B** 

proliferation of the activated lymphocytes and is typical for the acquired immunity.

starts to release soluble factors known as cytokines (Stevenson et al., 1990).

viruses and fungi.

Szczepanik 2006).

**2.2 The cells and mechanism of the acquired immunity** 

humoral and the cell mediated.

**2.1 The innate immunity** 

**lymphocytes/ plasma cells** is the synthesis and the secretion of antibodies associated with the components of the humoral response.

**Immunoglobulins (antibodies**) are formed by - two identical light (L) and the two identical heavy (H) chains. The main form of the immunoglobulins are described: one of them is presented on the membrane surface of the B cells as the antigen specific receptor (BCR). However, the other one exists as the soluble form and is produced by plasma cells. The biologic results of the antigen-antibody reactions include many consequences such as agglutination with soluble antigen, as well as precipitations and activation of complement that results in the neutralization of bacterial toxins and microorganisms activity.

The activation of the B cells starts through the B cell receptor ( BCR) at the cell membrane and triggers the intracellular signaling pathways regulating the transcription of antibodies and cytokines genes (Coico & Sunshine 2009). The BCR has the exceptional ability to react with many different types of antigens such as peptides DNA, lipids and carbohydrates.

**The T lymphocytes** are a part of the **cell-mediated** immunity and their role is the cytokines production and support of the B cells activation. The T lymphocytes are divided into following subsets: h*elper (Th), cytotoxic (CCTL), regulatory (T reg) and memory (Tm).*  Similarly B cells and the T cells also have the antigen binding receptor on their surface (TCR) but in contrast to the BCR, the TCR interacts with small fragments of antigenic proteins called peptides which are presented on APC in association with class I and class II molecules included MHC.

**The major histocompatibility complex (MHC)** in the humans called human leukocyte antigen (HLA) has many different diverse immunological and non-immunological functions. The MHC is divided into two types of molecules encoded by the MHC classes: MHC class I and MHC class II. Both of them are recognized by different subsets of the T cells.The MHC class I molecules have the crucial task of the presentation of an antigenic protein to the T Cytotoxic lymphocytes (CD8+) while MHC class II presents an antigen to T Helper lymphocytes (CD4+). Molecules of MHC class I are found on the surface of all nucleated cells of human body while molecules of MHC class II are found on the surface of the APC *(*Coico & Sunshine 2009*).* The MHC complex includes the most polymorphic genomes in the human genomes with many consequences related to the transplantation and the autoimmune disease. It turned out that the human leukocyte antigen HLA-B27 is tightly correlated with the frequency of the spondylarthritis (Cauli et al., 2002; Jin & Wang, 2003). The adhesion molecules CD4+ and CD8+ are necessary to enhance the binding of the T cells and the APC. The expression of CD4+ and CD8+ is variable on the T cells. The normal ratio of CD4+ T cell to CD8+ T cells is approximately 2:1 in healthy population.

**The dendritic cells (DC)** are classical, the most potent APC and by this way they contribute to connection between the innate and acquire immune systems. The dendritic cells present the ability to initiate several immune responses such as stimulation of T and B lymphocytes and the resistance against various infections and cancer cells (Bodey et al., 1997).

**Cytokines** are produced by all cells of the human immune system. Cytokines form a complex network secretory molecules which exert their effects on the phases of the immune response. Cytokines are immensely responsible for the transduction of information among the immune system cells and are the very important components of the bi-directional communication between the immune and the neuroendocrine systems (Lisowska et al., 2008). Depending on the prevailing effects of inflammatory response they are called as a pro-inflammatory or anti-inflammatory. The pro-inflammatory cytokines are mainly

The Stress Response and Its Functional Implications in the Immune

(Baatar et al., 2009; Hattori, 2009).

**2.4 The inflammatory response** 

(Blackburn, 2011; Jakob & Stanga, 2010; Wahr, 1999).

Response After Surgery in Patients with Chronic Inflammation Undergoing Arthroplasty 19

Norepinephrine and dopamine can also increase the activation and the proliferation of T cells. Moreover, norepinephrine modulates the innate immune response e.g. by the inhibition of tumor necrosis factor (TNF) synthesis. TNF and IL-1β are classical pro-

The different types of stress is associated with high production of catecholamines and corticosteroids cause immunosupression. Both hormones can inhibit the production of interferon gamma ( IFN-γ) and simultaneously stimulate the production of the antiinflammatory cytokines: IL-4, IL-10 by the T helper cells via adrenergic receptors. The stimulation of the β2-adrenergic receptors on CD4(+) T lymphocytes cause the inhibition of their proliferation and the cytokines secretion (Riether et al., 2011; Salicrú et al., 2007). The another example of bidirectional correlation between the immune and the neuroendocrine system is the ghrelin secreted primarily by the stomach and intestine cells. Although, it should be noted that the hypothalamus, the pituitary gland and the other peripheral organs can also be the source of the ghrelin. The ghrelin acts on the other, however expresses many immunological functions through the growth hormone receptor expressed in many immune cells include the T lymphocytes,the B lymphocytes, monocytes and neutrophils. In addition, the ghrelin is known as the anti-inflammatory mediator and seems to have an opposite effects to the TNF while modulation of the immune response

Ghrelin acts on other immune cells such as the T lymphocytes, the B lymphocytes, monocytes and neutrophils via the growth hormone receptor via and shows the anti-

**Metabolic response** is also induced by the surgery trauma: However, depressed during first hours after the surgery in next phase is characterized by increase of catabolism and hypermetabolism with gluconeogenesis lasting 3-4 days. Metabolic changes induced by the surgery trauma are the part of the systemic reaction that includes a wide range of endocrinological, immunological and hematological effects. Perioperative metabolic changes described as the hypermetabolism include rapid increased oxygen consumption. Postoperatively, hypermetabolism is associated with increased glucose serum level, lactates and free fatty acids. The electrolytes disturbance takes important part while the metabolic response. Lower serum potassium level is the predictor of a serious perioperative arrhythmia and hypoproteinemia as well as it can disturb the process of wound healing

The inflammatory response is the fundamental type of response against various situation like e.g. trauma or infection and it is focused on stimulation of various parameters which are essential for the wound healing, the protection against infection and the maintenance of homeostasis. The acute inflammatory response to surgery trauma can be prescribed as the combination of the neurological stimulation with the metabolic changes trigger release of the molecules of the local inflammation such as histamine, kinins and prostaglandins with increasing capillary permeability which allows leucocytes and lymphocytes the infiltration into injury site. The pro-inflammatory cytokines such as IL-1, IL-6, TNF-α are released from immune cells, their concentration correlate with the length of surgery therefore they are considered as an indicator of stress severity (Cruickshank et al., 1990; Norman & Fink, 1997). The function of cytokines focusing on communication between cells in both the paracrine and the endocrine way. Pro-inflammatory cytokines (IL-6, TNF, IL-1) are potent

inflammatory action in inflammatory response (Himmerich & Sheldrick, 2010).

inflammatory cytokines secreted mostly by monocytes *(*Torres et al., 2005).

represented by interleukins: IL-1, IL-6, TNF, IL-2, IL-6, IL-8, IL-15. The examples of the antiinflammatory cytokines are interleukins IL-4, IL-10, TGF-. Cytokines may act locally or systemically by cell to cell signaling. The action of cytokines can be described as autocrine, paracrine or endocrine. Some cytokines are known to act in either synergistic or antagonistic way. Cytokines may affect the action of each other which may give synergistic or antagonistic effect on the targeted cells. Both the synthesis and activity of cytokines are regarded at different levels. Different type of antagonistic molecules (e.g. soluble receptor, cytokine binding proteins, molecules that compete with cytokine for binding to the receptors) are produced to restrict they activities. The potent pro-inflammatory activities of cytokines are restricted by three major systems that can prevent uncontrolled excessive production of cytokines. These relates to their synthesis and release membrane receptors and intracellular signal transduction (Weber et al., 2010). Both overproduction and underproduction of cytokines and their receptors take place in many diseases with prevailed acute or chronic inflammatory state.

### **2.3 The interdependence between the neuroendocrine and the immune system whilst direct response to surgery stress**

**The surgical stress**" can be described as a various alterations inside organism undergoing surgical procedure. The tissue damage caused by surgery leads to activation of the immune system and the early inflammatory response and directly correlates with the degree of tissue damage. A full-fledged systemic inflammatory reaction results in stimulation of the four major programs: the acute-phase reaction, the sickness syndrome, the pain program and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. The cooperation between the autonomic nervous system and the hypothalamic-pituitary adrenal axis (HPA axis) is important to dampen the reaction of the immune system.

The response to trauma consists of the hormonal as well as the immunological and the metabolic responses**.** The host response is mainly characterized by increased secretion of various hormones such as: cortisol, catecholamines, ADH (antidiuretic hormone), glucagon and growth hormone.

The direct afferent impulses from surgery site release several factors which strongly activate hypothalamus for corticotropin releasing hormone (CRH) secretion which in turn stimulates the pituitary gland to release its typical hormones. The potent correlation exist between concentration of hormones such as ACTH, cortisol, ADH and intensity of the surgical stress. The neurogenic stimuli from surgery site can be ceased by central blockade such as the spinal and the epidural anesthesia. The immune system and the neuroendocrine system influence each other via molecules and receptors shared by both systems. Activation of the neuroendocrine system results in alteration of the host homeostasis and the immune response including cytokine production.

Somatostatin and catecholamines are the basic examples of the mentioned correlation. Somatostatin (SS) is an endogenous peptide widespread distribute related with five known somatostatin receptors (sst1-5) which are usually expressed on the surface of the immune cells and on central and peripheral neurons as well. The SS is found in the central nervous system, the gastrointestinal tract and endocrine glands. Moreover, macrophage, endothelial cells and lymphocytes express high affinity receptors for the somatostatin *(*Armani et al., 2007; Dalm et al., 2003; Ferone et al., 2006).

Norepinephrine and dopamine can also increase the activation and the proliferation of T cells. Moreover, norepinephrine modulates the innate immune response e.g. by the inhibition of tumor necrosis factor (TNF) synthesis. TNF and IL-1β are classical proinflammatory cytokines secreted mostly by monocytes *(*Torres et al., 2005).

The different types of stress is associated with high production of catecholamines and corticosteroids cause immunosupression. Both hormones can inhibit the production of interferon gamma ( IFN-γ) and simultaneously stimulate the production of the antiinflammatory cytokines: IL-4, IL-10 by the T helper cells via adrenergic receptors. The stimulation of the β2-adrenergic receptors on CD4(+) T lymphocytes cause the inhibition of their proliferation and the cytokines secretion (Riether et al., 2011; Salicrú et al., 2007).

The another example of bidirectional correlation between the immune and the neuroendocrine system is the ghrelin secreted primarily by the stomach and intestine cells. Although, it should be noted that the hypothalamus, the pituitary gland and the other peripheral organs can also be the source of the ghrelin. The ghrelin acts on the other, however expresses many immunological functions through the growth hormone receptor expressed in many immune cells include the T lymphocytes,the B lymphocytes, monocytes and neutrophils. In addition, the ghrelin is known as the anti-inflammatory mediator and seems to have an opposite effects to the TNF while modulation of the immune response (Baatar et al., 2009; Hattori, 2009).

Ghrelin acts on other immune cells such as the T lymphocytes, the B lymphocytes, monocytes and neutrophils via the growth hormone receptor via and shows the antiinflammatory action in inflammatory response (Himmerich & Sheldrick, 2010).

**Metabolic response** is also induced by the surgery trauma: However, depressed during first hours after the surgery in next phase is characterized by increase of catabolism and hypermetabolism with gluconeogenesis lasting 3-4 days. Metabolic changes induced by the surgery trauma are the part of the systemic reaction that includes a wide range of endocrinological, immunological and hematological effects. Perioperative metabolic changes described as the hypermetabolism include rapid increased oxygen consumption. Postoperatively, hypermetabolism is associated with increased glucose serum level, lactates and free fatty acids. The electrolytes disturbance takes important part while the metabolic response. Lower serum potassium level is the predictor of a serious perioperative arrhythmia and hypoproteinemia as well as it can disturb the process of wound healing (Blackburn, 2011; Jakob & Stanga, 2010; Wahr, 1999).

### **2.4 The inflammatory response**

18 Recent Advances in Arthroplasty

represented by interleukins: IL-1, IL-6, TNF, IL-2, IL-6, IL-8, IL-15. The examples of the antiinflammatory cytokines are interleukins IL-4, IL-10, TGF-. Cytokines may act locally or systemically by cell to cell signaling. The action of cytokines can be described as autocrine, paracrine or endocrine. Some cytokines are known to act in either synergistic or antagonistic way. Cytokines may affect the action of each other which may give synergistic or antagonistic effect on the targeted cells. Both the synthesis and activity of cytokines are regarded at different levels. Different type of antagonistic molecules (e.g. soluble receptor, cytokine binding proteins, molecules that compete with cytokine for binding to the receptors) are produced to restrict they activities. The potent pro-inflammatory activities of cytokines are restricted by three major systems that can prevent uncontrolled excessive production of cytokines. These relates to their synthesis and release membrane receptors and intracellular signal transduction (Weber et al., 2010). Both overproduction and underproduction of cytokines and their receptors take place in many diseases with

**2.3 The interdependence between the neuroendocrine and the immune system whilst** 

**The surgical stress**" can be described as a various alterations inside organism undergoing surgical procedure. The tissue damage caused by surgery leads to activation of the immune system and the early inflammatory response and directly correlates with the degree of tissue damage. A full-fledged systemic inflammatory reaction results in stimulation of the four major programs: the acute-phase reaction, the sickness syndrome, the pain program and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. The cooperation between the autonomic nervous system and the hypothalamic-pituitary adrenal axis (HPA axis) is important to dampen the reaction of the

The response to trauma consists of the hormonal as well as the immunological and the metabolic responses**.** The host response is mainly characterized by increased secretion of various hormones such as: cortisol, catecholamines, ADH (antidiuretic hormone), glucagon

The direct afferent impulses from surgery site release several factors which strongly activate hypothalamus for corticotropin releasing hormone (CRH) secretion which in turn stimulates the pituitary gland to release its typical hormones. The potent correlation exist between concentration of hormones such as ACTH, cortisol, ADH and intensity of the surgical stress. The neurogenic stimuli from surgery site can be ceased by central blockade such as the spinal and the epidural anesthesia. The immune system and the neuroendocrine system influence each other via molecules and receptors shared by both systems. Activation of the neuroendocrine system results in alteration of the host homeostasis and the immune

Somatostatin and catecholamines are the basic examples of the mentioned correlation. Somatostatin (SS) is an endogenous peptide widespread distribute related with five known somatostatin receptors (sst1-5) which are usually expressed on the surface of the immune cells and on central and peripheral neurons as well. The SS is found in the central nervous system, the gastrointestinal tract and endocrine glands. Moreover, macrophage, endothelial cells and lymphocytes express high affinity receptors for the somatostatin *(*Armani et al.,

prevailed acute or chronic inflammatory state.

**direct response to surgery stress** 

immune system.

and growth hormone.

response including cytokine production.

2007; Dalm et al., 2003; Ferone et al., 2006).

The inflammatory response is the fundamental type of response against various situation like e.g. trauma or infection and it is focused on stimulation of various parameters which are essential for the wound healing, the protection against infection and the maintenance of homeostasis. The acute inflammatory response to surgery trauma can be prescribed as the combination of the neurological stimulation with the metabolic changes trigger release of the molecules of the local inflammation such as histamine, kinins and prostaglandins with increasing capillary permeability which allows leucocytes and lymphocytes the infiltration into injury site. The pro-inflammatory cytokines such as IL-1, IL-6, TNF-α are released from immune cells, their concentration correlate with the length of surgery therefore they are considered as an indicator of stress severity (Cruickshank et al., 1990; Norman & Fink, 1997). The function of cytokines focusing on communication between cells in both the paracrine and the endocrine way. Pro-inflammatory cytokines (IL-6, TNF, IL-1) are potent

The Stress Response and Its Functional Implications in the Immune

adhesion molecules (ICAM)) (Lenzab et all., 2007; Lenz et al., 2007).

enables the infiltration of leukocytes from the bloodstream into the tissues.

**4. The influence of regional anesthesia for stress surgery response** 

immune system or significant immunosupression caused by the surgery trauma.

The choice of anesthesia type as well as technique relates to influence on the immune response and may be important in patients with immunological disorders. This situation occurs in patients with immune system deficiency. Patients suffer from immune system disturbances, due to autoimmune or cancer diseases, appear to require special consideration. Among this group of patients should be expected the pathological reaction of

The imbalanced immune system can modulate the neuroendocrine system and inflammatory responses to the surgery trauma in terms of production of cytokines, immunoglobins, proliferation of lymphocytes, and phagocytosis monocytes/macrophages. The choice of regional anesthesia techniques allow to avoid the supply of volatile/ intravenous anesthetics agents and the controlled ventilation procedures. Furthermore , the afferent nerves blockade is associated with attenuation of the hormonal response to the surgery stress. The regional anesthesia techniques have a significant effect on the immune

but not antagonist.

Nishimoto, 2006).

& Hall, 1997).

fibroblasts, and the activated T cells.

(TNF).

Response After Surgery in Patients with Chronic Inflammation Undergoing Arthroplasty 21

The receptor for IL-6 consists of two proteins: the chain α, that can be expressed on membrane cell or in soluble form and subunit gp130 that belongs to proteins receptor for IL-6 in membrane cells. In contrast to most cytokines (e.g. TNF) soluble IL-6 acts as agonist

IL-6 play important role in many inflammatory diseases. RA is characterized by the overproduction of IL-6. The very high level of IL-6 in the serum and synovial fluid is involved and correlated with clinical and laboratory indices (Lisowska et al., Dec 2007;

The secretion of both, described cytokines (IL-1, IL-6) is stimulated by tumor necrosis factor

**Tumor necrosis factor -** is produced by monocytes, macrophages, neutrophils, mast cells,

TNF is a number of TNF family. The binding of TNF to its receptors TNFR1 and TNFR2 cause multiple effects including: the increase of inflammatory mediators (e.g. nitric oxide (NO), arachidonic acid pathway, the platelet activating factor (PAF) and intracellular

The increased expression of TNF occurs in the synovium of rheumatoid arthritis patients with following induction of its cells activities. TNF is thought to play the role key role in the local activation of immune cells and joint cartilage and bone destruction. Together with IL-1 TNF-α also induce an expression of adhesion molecules on the surface of the endothelial cells which is particularly important during the first stages of inflammation, because it

**Transforming growth factor –β** (TGF–β) belongs to the TGF family cytokines. The TGF-β plays crucial role in inhibition of the inflammatory reaction and autoimmune diseases. The TGF–β plays the essential role in control and regulation of the lymphocytes proliferation, differentiation and survival. The TGF function including the antiproliferation activity on the T, B lymphocytes that can initiate and aggravate the disease. The TGF-β is also an important regulator of the B cell activation and differentiation (Li et al., 2006). Most of the produced cytokines are not stored at all. Nevertheless there are produced and released as needed. However, transforming growth factor β is stored inside the mast cells and platelets *(*Sheran

inducers of acute phase proteins (APPs). Among some (e.g. C-reactive protein (CRP), complement factors, fibrinogen, plazminogen CAPPs) are up- regulated while production of others (albumin, transferrin, antitrombin) decreased (Engler, 1995).

The long-lasting inflammatory process called chronic inflammatory response, itself is a organism wasting disease. The presence of the chronic inflammatory state is immensely associated with the dysfunction of the neuroendocrine-immune system. The neuroendocrine -immune disturbances also play an crucial role in the development of human autoimmune diseases such as the rheumatoid arthritis and the systemic lupus erythematous and the others. During the chronic inflammatory stage all these systems have become deficient.
