Inflammation

Inflammation classically describes four key signs - each of which have a latin derivation. Calor or heat, dolor or pain, rubor or redness, and tumor or swelling. Sometimes these four signs combine to cause a fifth sign, which is functio laesa or temporary loss of function due to pain or swelling. Okay - so inflammation usually starts with some stimuli, like a pathogen. Now, even though pathogens are a common cause of infection which can lead to inflammation, inflammation can be caused by other things as well like toxins and trauma. For example, after an intense workout, your muscles may feel sore - that’s due to inflammation trying to repair your overused muscle fibers. Ultimately, the goal of inflammation is to respond to the stimuli and restore balance. Oftentimes that includes eliminating the cause of tissue injury, clearing out necrotic or dead cells, and starting tissue repair. Broadly speaking, inflammation can be triggered by external and internal factors.

External factors can be non-microbial or microbial. Non-microbial factors include allergens, irritants, and toxic compounds. Now, the two main microbial factors that trigger inflammation are virulence factors and pathogen associated molecular patterns or PAMPs. Virulence factors are molecules that help pathogens colonize tissues and cause infection. PAMPs are small molecules with conserved patterns that are shared across many different pathogens, including bacterial wall components like peptidoglycan, lipopolysaccharide or LPS, and lipoteichoic acid, and fungal wall components like mannan. For intracellular pathogens, like viruses, PAMPs might include the viral RNA or DNA. Our immune system recognizes virulence factors and PAMPs as foreign substances, and can trigger an inflammatory response against them.

Now, in terms of internal factors, it turns out that there’s an endogenous equivalent to PAMPs, called damage associated molecular patterns or DAMPs. DAMPs are intracellular proteins that get released when a cell’s plasma membrane is injured or when a cell dies. So DAMPs are a signal that there’s serious cell damage and they trigger inflammation. Now, PAMPs and DAMPs are recognized by Pattern Recognition Receptors or PRRs, which are cell surface receptors on various leukocytes that help to activate those cells and spark the inflammatory response, which can be thought of as the innate immune system. Key features are that this response is non-specific - meaning that PRRs don’t distinguish one specific pathogen from another, although they can distinguish between broad categories like viruses from bacteria. Also, the response is really fast - occurring within minutes to hours, and there’s no memory associated with innate responses.

Generally speaking, there are two main types of leukocytes: granulocytes which include neutrophils, eosinophils, basophils, and mast cells and agranulocytes which include lymphocytes and monocytes, which can differentiate into macrophages or dendritic cells.

The inflammatory process usually begins with either macrophages or mast cells, both of which are found in the tissues. When there’s tissue damage, these cells respond to the PAMPs or DAMPs. Mast cells have granules containing different inflammatory mediators like histamine, serotonin, cytokines, and eicosanoids, such as prostaglandins and leukotrienes. These inflammatory mediators act on the endothelial cells surrounding the capillaries nearby, causing them to separate from each other. In addition, macrophages - which are the garbage truck of the body - begin to eat up invading pathogens. The release of cytokines causes capillaries to get larger, and increase vascular permeability, allowing plasma proteins and fluids to leave the circulation. Endothelial cells also help spur on this process by releasing nitric oxide, which helps vasodilate the capillaries and make them more permeable. In addition, endothelial cells express more adhesion proteins to help leukocytes that are floating by in the blood to attach and roll along the vessel wall until they reach the injured site. In particular, neutrophils get attracted to the site of infection by the chemokines and microbial products. The neutrophil then begins to squeeze through the gaps between two endothelial cells, until it reaches the other side - this is called extravasation. It’s a bit like squeezing between two fence poles to sneak into an amusement park, rather than paying admission. Not saying that you should do that.