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Inflammation

Definition

Inflammation is by definition a defensive reaction of the body with the aim of eliminating the trigger of the inflammation and repairing the damage caused, either by restoring the tissue of origin (restitutio) or by a replacement tissue, the scar (reparatio).

Trigger

Inflammation is triggered by any stimuli, called 'noxae', that overcome the organism's defence-compensation mechanisms. By definition, a noxious agent is a substance or event that causes damage to a biological organism. The noxious agent can be divided according to its origin into internal and external, and according to its structure into physical, chemical or biological triggers (Table 1.1).

Defence Cascade of the Body

Numerous defence mechanisms exist to protect an organism. These are particularly effective at the 'contact surfaces' between the organism and the environment. There, the penetration of the noxious agent is prevented by mechanical as well as biological defence mechanisms.

The skin prevents the penetration of the noxious agent under physiological conditions due to its structural design. For this purpose, the skin consists of different layers with different functions (Figure 1.1).

The outer layer of the skin, the epidermis, is made up of the layers - stratum corneum, lucidum, granulosum, spinosum and basale from the outside inwards. The main cell type in the epidermis is the keratinocyte. This differentiates in the stratum basale from epidermal stem cells. In the stratum spinosum, the cells begin to remodel with an increase in volume and a change in shape and width. In the further course, keratohyalin grains are formed in the stratum granulosum, and further remodelling processes take place. The cells become flattened, the nucleus is lost, shrinkage occurs due to fluid loss, and finally cornification takes place. Eventually, no more keratinocytes can be detected in the stratum corneum. Keratinocytes become corneocytes. The cornification process builds up a mechanical protection for the skin. In addition, penetration of a noxious substance is ensured by a close connection between the keratinocytes through tight-junctions. The tight-junctions consist of connections of transmembrane proteins, such as claudin and occludin. Intracellularly, these proteins are connected to the cytoskeleton. The tight-junctions connect the cells into a bandage that forms a barrier to the paracellular penetration of a noxious agent.

In addition, defence cells such as Langerhans cells are localised in the epidermis.

These are tissue macrophages that are capable of phagocytosis but also differentiate into antigen-presenting cells after contact with an antigenically active noxious agent, which can initiate an immune response.

Finally, the extracellular matrix in the epidermis forms a molecular association that can prevent the penetration of a noxious agent. The molecules of the extracellular matrix include, for example, keratins and collagens as structural proteins and ceramides, which are lipids composed of a sphingosine molecule and fatty acids that provide protection against hydrophilic noxae (Mitamura et al. 2021) (Table 1.2).

Table 1.1 Common causes of inflammation in dogs and cats.

Physical Chemical Biological Infectious agents Heat Environmental toxins Viruses Cold Endogenous toxins Tumours Bacteria Degenerations Fungi Parasites

Figure 1.1 Structure of the outer skin and development of keratinocytes.

Table 1.2 Components of the epidermal extracellular matrix with function.

Molecule Function Keratin Intermediate filament, structural element of keratinocytes Collagen Tight protein of the ECM, adhesion molecule Elastin Elastic protein of the ECM Fillagrin Structural protein Ceramide Hydrophobic protection

The mucous membranes of the body form the inner boundary layer between the organism and the environment. The microscopic structure of the mucous membranes already reflects defence competences. This includes the contact of the mucosal cells through tight-junctions. These form a tight connection between the cell membrane of neighbouring cells through proteins such as occludin. This prevents the paracellular penetration of extracorporeal noxae.

Another superficial defence mechanism is the synthesis of mucins. Mucins are glycoproteins that are synthesised by goblet cells and form a protective layer several micrometres thick on the mucosa. In the process, defence functions of the mucins develop due to their gel-like structure, which enables mechanical protection of the underlying mucosal cells. Chemically, for example, bicarbonate residues of the mucins can bind and inactivate acids, and biologically, mucins can prevent bacteria from invading by binding them.

Cells localised in the mucosa (Paneth cells) secrete lysozyme or defensins to inactivate germs. The latter are differentiated into a-, ß- and ?-defensins based on their molecular structure (Lehrer and Ganz 2002).

The effects of defensins are antimicrobial and immunomodulatory. The former effect is based on their positive molecular charge, which enables a charge-dependent interaction with the negatively charged bacterial cell wall, especially the lipopolysaccharides (Scott and Hancock 2000). The binding of the defensins results in pore formation. The consequence is a depolarisation of the bacterial cell membrane and thus a breakdown of the membrane potential and lysis of the cell (Scott and Hancock 2000; Sahl et al. 2005).

In addition, defensins show immunomodulatory functions. Defensins have a chemotactic effect on dendritic cells and memory T cells, and thus represent a link between innate and adaptive immune responses. In addition, some defensins act chemotactically on monocytes and macrophages, and in some cases induce mast cell activation and degranulation. As a result, histamine and prostaglandins are released, which promote the migration of neutrophilic granulocytes. Degranulation of the recruited neutrophilic granulocytes in turn releases defensins again, resulting in a positive feedback loop (Yang et al. 2002).

The secretion of lysozyme is another defence mechanism against bacterial invasion of the mucous membranes. Lysozyme is an enzyme that cleaves murein. Murein is a peptidoglycan and a component of the bacterial cell wall. Due to the hydrolytic cleavage of murein, the bacterial cell wall loses its selective permeability and rupture of the bacterial cell wall occurs due to increased water influx.

Another defence mechanism in the mucosa is the mucosa-associated lymphoid system located in the lamina propria, which is called 'gut associated lymphoid tissue' (GALT) in the gastrointestinal tract and bronchial associated lymphoid tissue (BALT) in the respiratory tract. This system includes numerous cells of the non-specific and specific defence response, such as macrophages and lymphocytes (Figure 1.2).

Figure 1.2 Building up the defence system of the mucous membrane.

Player of the Inflammation

The inflammatory process is maintained by some so-called 'inflammatory cells'. These combine some properties that predispose them to fulfil the definitional task of inflammation. This states that inflammation is a reaction of the body that serves to eliminate a noxious agent and its consequences.

The following cells are involved in the inflammatory process:

Neutrophilic granulocytes originate from the leukocyte pool of the bone marrow and are distributed throughout the blood. The residence time in the blood is a few hours (6-12?hours). Subsequently, the neutrophilic granulocytes leave the blood capillaries under the influence of chemoattractive substances. These are released as part of the local inflammatory process. The process of neutrophilic granulocyte emigration from the blood vessels takes place via adhesion and transmigration. Integrin-mediated, the neutrophilic granulocytes adhere to the surfaces of the endothelial cells. In the process, the cells change their shape from roundish to an amoeboid cell shape. The cells can now migrate trans- and paracellularly through the vascular endothelial layer.

In the area of inflammation, the neutrophilic granulocytes have different functions. The ability to phagocytose allows the cells to take up and lyse the noxious agent (e.g. bacteria). For this process, the noxious agent is taken up by membrane invagination and the resulting vesicle combines with the granular structures of the granulocyte. In...