**3.1 Pathophysiology of appendicitis**

Exact pathophysiology of appendicitis itself remains a struggle for physicians. The process of appendicitis itself is related and basically similar to other pathophysiology of inflammations. Commonly appendicitis began with a luminal obstruction. Several causes of obstruction may occur such as lymphoid hyperplasia, parasitic infections, fecalith, or intra and extra luminal mass. This causes an increase of intraluminal and intramural pressure which causes small vascular and lymphatic occlusion collapsed by the tension of the lumen and mural. Obstructed appendix tends to cause overgrowth of bacteria, mostly aerobic bacteria dominate in acute appendicitis [16].

The obstruction may also cause mucous plaques and accumulated causing distension. Distension of the appendix may progress vary from one patient to another up to 50–65 mmHg. When the luminal pressure increases, vascularization in the mural may be disrupted. Increase in the pressure may beyond the lymphatic and venous pressure and prevents fluid drain from the two vessels due to a weak wall of vein and lymphatics [17]. First collapsed vessel would be the lymphatic drainage preventing fluid back into circulation to remain in the appendix tissue. Soon as pressure increases in the lumen, the pressure disrupted the lumen of the vein and causes collapse of both lymph and blood flow from the tissue of the appendix. This process causes the edema process which occurred by disrupted fluid drainage [14, 18].

This state of appendicitis consisted of inflammation and edema alone possibly start the clinical symptoms of appendicitis, but this stage is considered as a mild process in which conservative treatment for appendicitis may be available. Surgical treatment may be offered, and still may be beneficial but as it is an invasive procedure and has a number of complications, the surgical procedure which is still not yet urgent to be performed may not be a favorable choice of treatment. Antibiotics and good fiber intake may be one of the choice and helps relieve symptoms and reduce the inflammation of appendicitis [5, 19].

But the mild state of appendicitis also has a risk to develop further. Fluid accumulation and edema also cause more tension to the vascular wall causing further obstruction and disruptions of vessel flows. Soon as the pressure increases more the arterial walls were collapsed due to pressure to its wall. The blood flow containing oxygens and nutrients was decreased due to arterial obstructions. This stated the condition of hypoxia in the distal of the arterial obstruction in the appendix [20].

Hypoxia state of the mucosa and the wall of the appendix begins further tissue damage in the appendix. Tissue damages were due to hypoxic stress of the cells in the appendix which then undergo a cell apoptosis process of even necrosis of the tissue. Tissue damage causes less strength of the appendix wall from distensions of the edema and fluid accumulation that is then related to complications by ulcerations, perforations, and necrotic appendix. This process occurs only if the vascularization were disrupted. Hypoxic environment also tends to be favorable for growth of intestinal flora mostly the Gram-negative bacterias such as *Escherichia coli, Enterococcus, Bacteroides,* and *Pseudomonas*. Bacterial growth also elicits more inflammatory and immunologic processes in the appendix itself. *E. coli* itself as the main flora normal in the large intestine may cause activity changes and be pathogenic as shifted and trapped in the appendix with different microenvironments and releases toxins exacerbates inflammation [13, 20].

The tissue damage and necrosis in appendicitis risk a thin and fragile wall of the appendix. This at one point with more pressure would lead to a tear of the mucosal or even the muscular and serous layer of the wall causing perforation of the appendix. Once a perforation occur, acute appendicitis occurred with complication. As bacterial overgrowth inside the lumen of the appendix came in contact with the sterile peritoneum cavity begins further immune and inflammatory responses cause peritonitis. As peritonitis occurred in complicated appendicitis, operative treatment with laparotomy may be inevitable. Further inflammatory process of the peritoneal wall also risks the spread of bacteria into the bloodstream and may complicate more into sepsis with all its high risk of mortality [21, 22].

Bacterial growth causes inflammation, especially in the mucosa of the appendix. The incompetence of the appendiceal wall risk the development of spreading infections and inflammatory mediators causing inflammation of the serous layer of the

### *Endothelial Dysfunction in Appendicitis DOI: http://dx.doi.org/10.5772/intechopen.107480*

appendix. A close anatomical layer of the serous into the parietal peritoneum and other adjacent organs. The inflammation of the peritoneum led to appendicitis complicated with peritonitis. Stimulation of pain fibers of the afferent visceral pain nerves in the layer of the peritoneum to the level of medulla spinalis. Pain sensation is interpreted as epigastric and periumbilical pain, which quality could not be specifically localized, but the right lower quadrant has the most accumulation of inflammatory mediators that would inflame more and be more painful [12, 20].

Untreated and uncompensated process of inflammation leads the more serious complications of appendicitis. The longer the hypoxia occurs to the tissue, the more risk of tissue damage. Risk of infarction multiplied by time followed by progression into perforated or even gangrenous appendicitis. More severe symptoms as mentioned previously would progress and limits daily activity. More pain and nausea and vomiting would occur. Systemic involvement in sepsis may be part of the risk of prolonged appendicitis. The process and pathophysiology off appendicitis may be illustrated in **Figure 3** [16, 22].

Basically, no major changes occur in mesenteric circulation in appendicitis. However, as a reaction to inflammation, local vascularization specifically targeting the inflamed tissue increased and was hypothesized to activate the neovascularization in the collateral circulations nearby mucosa and muscular layer of the appendix. The tiny new collateral vasculature along the local inflammation we aimed to increase perfusion into the center of inflammation, which is highly fragile and requires

**Figure 3.**

*The pathophysiology of appendicitis [23].*

strong endothelial stability which may be supported by certain endothelial factors to maintain perfusion against high intraluminal pressure from the appendix itself and preventing collapsed or burst of the vascularization [23, 24].

Severity and complications of appendicitis are known to be related with necrosis or ischemic tissue in the appendix vermiform. Basic consideration on factors affecting the vascularization patency to tissue damage in appendicitis. Arteries with dysfunctioned endothelium occasionally damaged and unable to adapt and perform potent perfusion to tissues in systemic changes caused by the inflammatory mediators. While arteries with good endothelium tend to be able to keep strong perfusion to maintain oxygenation preventing cell death. This differentiates variations of symptoms in patients with appendicitis who develops complication and whom did not [25].

This means mucosal vascularization of the appendix was considered as a barrier preventing further damage to the mucosa from increased intraluminal pressure in appendicitis. So as the mucosal and muscular layer of the appendix receives adequate vascularization, tissue elasticity and cell regeneration would take place so that the tissue would able to adapt against stretch elicited by the increase of the intraluminal pressure. Furthermore, enough perfusion to the appendiceal muscular layer will be able to initiate appendiceal contractility to drain out fluid or any fecalith obstructing and causing trapped intraluminal contain. This tissue competence may be a key role in preventing the perforation of other complications of appendicitis [26].

#### **3.2 Recovery process in appendicitis**

The appendix as a rich in lymphoid tissue part of the intestine has a high reserve of natural killer cells (NK)111 CD31 T cells (NK T lymphocytes). This cell produces cytokines and chemokines early since activated by the local inflammatory process. Cells such as B2201CD31 T cells in the lymphoid of the appendix express CD45R indicates for T cell activations more than any part of the intestine. Certain factors related to a great number of lymphocytes in the appendix came as the presence of CCL21, a chemokine embedded to the lymphatic endothelial cells and luminal surface of endothelial venules around the parafollicular areas in MALT. CCL21 binds to CCR7 to promote recruitment of B and T lymphocytes to the appendiceal lymphoid tissue and migration of dendritic cells (DC) back to appendiceal lymph nodes [15].

Apart from the abundant lymphocytes in the appendix, the molecular expression on the surface of the lymphocytes in the appendix differs from lymphocytes in the intestinal lymphocytes. In the lamina propria, the T cells in the lamina propria of the appendix express more integrin subunit b7 than B cells and also than the lymphocytes in the other parts of the intestine. Integrin a4b7 is expressed on T cells located between lamina propria and epithelium, and on macrophages and dendritic cells located in the mucosa of the appendix [22]. The molecule binds to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which mediation process of "tethering and rolling" and "homing" attracts lymphocytes into it. The localized expression of these molecules of a4b7 is considered a trafficking signal. Conversely, the aEb7 is responsible for the retention of these lymphocytes, via binding with its ligand E-cadherin. The dendritic cells express aEb7 stimulate the differentiation of forkhead box protein 3 (FoxP3)1 Treg cells soon after the interactions with antigens. Therefore, the suppression of regulatory expression would prevent lymphocyte differentiation and lead to a proinflammatory state [14].

CD51 cells or B1 lymphocytes are expressed more in a healthy appendix than the rest of the gut. When the appendix inflamed, the expression increased even

#### *Endothelial Dysfunction in Appendicitis DOI: http://dx.doi.org/10.5772/intechopen.107480*

more. These CD51 B cells produce IgM antibodies specific to certain pathogens. The synthesis of the IgM could take place directly in case of the absence of antigen presentation by other T cells, similar to innate-like immune response expressed by IELs. Despite the ability to synthesize IgM similar to immune response, the IgM antigen has low affinities, it still has major importance in reaction to microorganisms. Increase in the expression would be explained by an alteration of the intestinal microflora that occurs along the pathogenesis of appendicitis. Moreover, the CD51 cells also produce anti-self antibodies and an anti-inflammatory molecule such as IL-10 which means the increase of the expression was process to prevent inflammation currently occurring [27].

Pathologically, the complications of appendicitis were affected by the mucosal resistance to stress and adequate vascularity (microvessel density) in the appendix mucosa. This prevents further tissue damage. The mucosal resistance is determined by its adequacy to regenerate in case of stress or damage, producing new and strong mucosal layer which is influenced by folic acid (FA) metabolism. Adequate vascularity is then determined by ability of angiogenesis which plays as on of the most important factors in wound healing process. The angiogenesis itself is induced by growth factors namely vascular endothelial growth factor (VEGF), which role is fundamental by mediating and inducing the neovascularization, reepithelialization, and regulation of extracellular matrix. However the VEGF expression itself is endothelial cells in the blood vessels [28].

The angiogenesis occurs and induced in appendicitis, forming novel microvasculatures around the inflamed appendix to sustain adequate perfusion. The formation of new vascularization is required undergo the increased tissue's requirement of oxygen and nutrients of parenchymal remodeling, as well as to repair damaged blood vessels induced by pressure of inflammatory cytokines. Angiogenesis itself depends on VEGF, which is produced by damaged endothelial cells that stimulates mitosis in the endothelial lining of blood vessels creating new blood vessels other than currently damages vessel. This mechanism relates the VGEF to be believed associated with complicated appendicitis. Further evidence presented that different expression of VEGF may be found on histopathological examination of microvessel density in appendicitis specimens [28, 29].

Differentiating between risk of having complication may be a cut off on physician to take a concise decision on therapy of the patient. Patient which endothel may be strong enough responding the inflammatory process may not need to undergo operative treatment as tissue repair and remodeling were likely. However in chronic inflammation and weak endothelium possess a risk of further harm and requires surgical procedure [4, 12, 25].

Factors determining endothelial stabilities are regarding on tissue strength itself. Subgroup of individuals who tend to have a strong connective tissue subtypes of collagens has a chance to have a stronger endothelial stability. Factors effecting the endothelial growth and proliferations subsequently backs-up cells of the endothel to proliferate in preventing the endothelial damage. Also neovascularization may occur and possibly perfuse other sites of inflamed tissue to receive strong and supports of the vascularization. This prevents further complications to occur and more invasive treatment procedure may not be required or indicated as if antibiotics are capable [4, 19, 30]. The growth factor such as the vascular endothelial growth factor (VEGF) has a main role determining the strength of the endothelium against inflammation, especially in cases of appendicitis itself in the vascularization of the appendix [31].
