Mechanisms of Disease 1 HC11: Pathology of inflammatory reactions

HC11: Pathology of inflammatory reactions

Inflammation

Definition:

Inflammation is a reaction of a vascularized tissue to a pathogenic insult. It is characterized by the generation of inflammatory mediators and movement of fluid and leukocytes from the blood into extravascular tissues. It is a combination of:

  • Calor (heat)
  • Rubor (redness)
  • Tumor (swelling)
  • Dolor (pain)
  • Functio laesa (disfunction)

Inflammation can be divided into 3 categories:

  • Acute inflammation
  • Chronic inflammation
  • Granulomatous inflammation

Inflammation is necessary to fight pathogens. However, too much inflammation has negative consequences. This is the case in autoimmune diseases.

Players:

In the process of inflammation, 4 particles play an important part:

  • Segmented neutrophils
    • Neutral staining granules
    • Pink cytoplasm
    • Nucleus with condensed clumped chromatin and 3-5 lobes connected by thin chromatin filaments
  • Monocytes → macrophage
    • Kidney shaped nucleus with mature chromatin
    • Vacuoles are commonly noted
    • Low nuclear-to-cytoplasm ratio
  • Lymphocytes
    • Slightly larger than mature red blood cells
    • High nucleus to cytoplasm ratio
    • Round mature nucleus with clumped chromatin
    • Scant, light blue cytoplasm with no granules
  • Endothelium
    • A layer of flat cells on the inside of blood vessels

Causes:

Inflammation isn't the same as infection → not all inflammation is caused by infection, and not all infections cause inflammation. There are 4 things that can cause inflammation:

  • Infections
    • Bacterial
    • Viral
    • Fungal
    • Parasitic
  • Immune reactions
    • Allergy
    • Autoimmune disease
  • Tissue necrosis
    • Ischemia
    • Thermal injury
    • Chemical injury
    • Trauma
  • Foreign bodies
    • Dirt
    • Sutures
    • Et cetera

Process:

Inflammation starts with vascular changes:

  1. Increased blood flow needs to be slowed down → vasodilatation
  2. Vasodilatation leads to an increased permeability → fluid leaves the vessels
  3. The blood flow decreases → stasis
  4. Stasis causes thick blood vessels and edema
  5. Thick blood vessels cause redness and swelling at the place of infection
  6. Endothelial cells make openings with histamine and NO
    • This is a very fast process that occurs within minutes-hours
  7. In case of a bacterial infection, endothelial cells are damaged due to microbiological toxines → endothelium can't close anymore → the blood pressure decreases more
    • This can take hours to days
    • This can happen in case of mengingococcal septicaemia
  8. The goal of these vascular changes is to attract neutrophils, monocytes and lymphocytes to the place of infection or tissue damage:
    1. Leukocytes "land" on the epithelia because of their slow speed
    2. The leukocytes start to roll → make contact with the epithelia
    3. The leukocytes migrate through the epithelia
      • Neutrophils: are the first to arrive at the site of infection → endothelial cells already have binding spots for neutrophils in their cytoplasm
        • These binding points are called P-selectin/E-selectin, which are called Weibel-Palade bodies when they're still inside the endothelial cells
      • Monocytes: are the last to arrive at the site of infection → their binding spots have to be created, which takes a while

Leukocyte emigration:

In more detail, the process of leukocyte emigration goes as follows:

  1. A macrophage lives in tissue and meets a microbe → cytokines like histamine, NO and TNF are created
  2. Endothelial cells react to this by opening and making binding spots, to which the leukocytes can bind
    • This is stimulated by the already decreased blood flow → makes it easier for leukocytes to bind
    • Neutrophils arrive first, because they are the fastest
  3. The leukocytes start rolling from the binding points, until they are strongly bound by an integrin ligand
  4. Endothelial cells help the leukocytes (neutrophils) to enter the tissue
  5. In the tissue, leukocytes release chemokines
  6. Chemokines cause more cells to migrate to the inflammation site

Repair

An inflammation can lead to:

  • Full recovery
  • An abces
  • Chronic inflammation

There is a very delicate balance between inflammation and repair. Macrophages play a very important role. They arrive at the tissue and can differentiate in 2 different species:

  • Classically activated M1 macrophages: specialized in killing damaged cells
    • Also cause pathological inflammation
  • Alternatively activated M2 macrophages: specialized in repair
    • Create new tissue

The repairing process starts once the macrophages have cleaned up the inflammation. Repairing is done by:

  • Growth factors
  • Fibrogen cytokines → repairing creates scars
  • Angiogen factors
  • Remodeling collagen

Chronic inflammation:

In case of acute inflammation, lots of neutrophils will be present.  If the target cannot be cleaned, it is a case of chronic inflammation. This leads to:

  • Collateral damage of normal tissue
  • Attempts at healing
    • Replacement of damaged tissue with fibrosis
    • Proliferation of blood vessels

At this point, a more sophisticated strategy is necessary → an influx of lymphocytes. Chronic inflammation can lead to fibrosis and tissue-damage. Fibrosis is irreversible.

In conclusion, the biggest difference between acute and chronic inflammation is:

  • Acute inflammation: neutrophilic granulocytes with lobulated nuclei
  • Chronic inflammation: lymphocytes and fibrosis

Granulomes:

If things get really tough, a granulome arrives → a big ring surrounding the infection with T-cells on the outside and macrophages on the inside. The granulome is a very big cell and tries to limit the infection to one place. Granulomatic inflammation is always chronic. This happens in cases like TBC or if foreign bodies like silicone are ingested.

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