Inflammation is a hallmark of injury and infection. In fact, a wide range of stimuli can lead to inflammation including inflammatory mediators (e.g. cytokines, bacterial toxins, activated complement, enzymes), pathogens (e.g. bacteria, viruses, fungi, parasites), associated PAMPs (Pathogen Associated Molecular Patterns such as endotoxin and other bacterial components), physical injury (e.g. trauma, hemorrhage), chemicals (e.g. free oxygen radicals, acid or alkali), DAMPs (Damage Associated Molecular Pattern molecules such as HMGB1, ATP, mitochondrial DNA), thermal injury (burns, frostbite), and radiation (e.g. UV exposure, radiation therapy). All this leads to an uncontrolled immune response.
Inflammation is normally localized to the site of injury or infection but can spread systemically through the production and release of cytokines and other inflammatory mediators in the blood. This Systemic Inflammatory Response Syndrome (SIRS) can be adaptive, engaging the resources of the entire body to help the body combat the injury or infection and aid in healing. However, this SIRS response can also rapidly turn maladaptive, driven by a cytokine storm and causing widespread cell death, injury to vital organs, ultimately leading to multiple organ failure and death in many cases. Organ failure is the cause of nearly half of all deaths in the ICU today, for which there are no effective therapies.
Sepsis is an excellent example of the damaging effects of cytokine storm and the maladaptive SIRS response. Sepsis is characterized as an overzealous SIRS response to a serious infection. Live pathogens, bacteria killed by antibiotics, and a variety of pathogen-associated ligands or PAMPs (e.g. endotoxin, exotoxins, and nucleic acids) can potently activate immune cells, resulting in vigorous cytokine production and excessive inflammation. Severe sepsis (sepsis with organ dysfunction) and septic shock (severe sepsis with refractory hypotension) can result, leading to a high risk of death. In SIRS without infection (e.g. trauma, burn injury, pancreatitis, complications of surgery, and many others) a variety of DAMPs, cytokines, enzymes, and other factors are primary drivers of inflammation.
The damaging role of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and others in the maladaptive SIRS response has been well-studied. Less well-appreciated is the harmful role of excessive anti-inflammatory cytokines (e.g. IL-4, IL-10, IL1-ra) in these conditions. Often erroneously termed “good cytokines”, these anti-inflammatory cytokines mediate the compensatory anti-inflammatory response syndrome (CARS) and can lead to profound immune suppression, called “immune paralysis”, leading to a predisposition to nosocomial infections and poor healing.