Inflammation, pathobiology

The response of the organism, carried by the connective tissue and blood vessels, to an external or internal inflammatory stimulus with the purpose of eliminating or inactivating it and repairing the stimulus-induced tissue damage. Inflammatory stimuli can be caused by: e.g. living organisms, allergens, immune complexes, physical or chemical stimuli.

Cardinal symptoms of inflammation are Rubor, Calor, Tumor, Dolor, Functio laesa.

Initial phase: After overcoming the natural barriers and penetration of pathogens into cells or interstitial tissue of the organism, local activation of the inflammatory signal occurs. Repetitive molecular patterns of the pathogen surfaces, so-called PAMPs (Pathogen Associated Molecular Patterns), which bind to the Toll-Like-Receptors of the cells (TLR 1-10) especially of the macrophages, have turned out to be the recognition principle of the local and systemic foreign microorganisms. During phagocytosis of bacteria, a high molecular signaling complex, the inflammasome, is generated, which triggers the production of IL-1 and TNAF-alpha from inactive precursors by activation of caspase I, thus initiating the inflammatory response.

Vascular phase: Furthermore, local tissue mast cells are stimulated to release their granular contents. It is mainly the release of histamine that causes the initial hyperemia characteristic of all inflammatory reactions.

The inflammatory reaction begins with a change in the microcirculation at the site of tissue damage. It is linked to these vascular changes and therefore can only occur in vascularized tissue.

Arteriolar contraction: A few seconds after exposure to an inflammatory stimulus, nervous signals and chemical mediators (e.g. adrenaline) cause a short-term arteriolar contraction that lasts only seconds or minutes.

Vasodilation: The arteriolar contraction is followed by a phase of vasodilation. Capillary and venous hyperemia develops with such a high degree of capillary dilation that blood flow in the capillaries slows down to stasis.

In this phase, due to the dilatation of the vessels and contraction of the endothelial cells, pores are opened, which cause a massive permeability disorder and also allow larger protein bodies of the blood plasma to leak into the interstitium. Stasis is formed as early as 15-30 minutes after the onset of damage and allows endothelial contact of leukocytes normally floating in the central stream of blood vessels.

Margination: In this phase, the leukocytes literally stick to the endothelium, they no longer circulate freely with the blood flow. Due to the shear forces of the blood flow, they initially roll slowly on the endothelium (margination). The leukocytes then pass through the endothelium and transmigrate (diapedesis) through the vessel wall into the interstitium.

Leukocyte diapedesis: Four stages can be distinguished at the molecular level:

• The expression of selectins (E-, P- and L-selectin), mediates short-term binding, which is a prerequisite for the rolling of leukocytes on the endothelia, so that the leukocytes come into contact with chemotactic factors.
• Chemokines initiate the activation of leukocytes, which in turn activate adhesion molecules, integrins.
• Integrins mediate the step, firm binding to the endothelial surface.
• During transmigration (diapedesis), leukocytes literally squeeze through gaps between contracting endothelial cells and actively migrate into the interstitium. In the process, the basement membrane must first be lysed. In the interstitium, the concentration gradient of chemotactic factors then serves as a guide to the site of inflammation. Important endogenous chemotactic factors are products of the complement system (C5a), the prostaglandin/leukotriene system (LTB4) and the chemokines.

Important exogenous chemotactic factors are N-formyl peptides, which are formed only in bacterial protein metabolism.

Cell migration: Granulocytes move amoeboidly through the very dense matrix by enzymatically cleaving filamentous matrix molecules(collagen IV in the basement membrane, collagen I and collagen III or proteoglycans in the interstitium, and the elastic fibers) and numerous other cross-linked nonfilamentous matrix molecules. Cell-matrix adhesion is mostly mediated by integrins, which are directly linked to the cytoskeleton of the cell inside the cell. By contraction of the actin cytoskeleton, the cells draw their cell body with nucleus along the matrix molecules (reverse hand mirror shape).

Intralysosomal killing of pathogens: At the site of inflammation, pathogens are phagocytosed by macrophages(monocytes and neutrophil granulocytes. Phagocytosed pathogens can then be killed in phagoylsosomes of these cells and then degraded and digested. The following mechanisms are effective in this process:

• NADH oxidase complex which leads to the formation of active oxygen.
• Myeloperoxidase activates the formation of oxygen radicals and hypochloride ions.
• Other enzymes and proteins have bacteriostatic effects (e.g. alpha-defensins, lysozymes)
• Inducible NO synthase (INOS) forms active nitrogen radicals that inhibit cell metabolism and nucleotide synthesis of pathogens.

1. Müller JG et al (2018) General principles: inflammation as a local and systemic phenomenon. In: Grundmann, Kurzlehrbuch der Pathologie. Ed. Kirchner Th et al. Elsevier pp 138-142.