ADVANCED INFLAMMATORY PHYSIOLOGY
Next Unit: Cellular Components of Inflammation
22 minute read
Inflammation...the rest of the story
The immune system is organized into innate and adaptive immune responses, with adaptive immunity further subdivided into two branches, humoral and cell-mediated immunity.
Inflammation is part of the innate immune system.
After tissue has been damaged, it must undergo mechanisms that stop the damage while initiating and supporting subsequent repair of the tissue. Thus, inflammation and cellular repair are not two distinct processes, but represent an overlapping continuum in the dynamics of tissue health.
INFLAMMATION: the body's initial mechanism for dealing with the things that damage it, a protective response to rid the body both of the things injuring tissue and the necrotic debris (cells, mediators, etc.) that lie in the wake of the battle between host and invader.
Besides being a first line of defense against microbes, the innate immune system activates and instructs adaptive immune responses, regulates inflammation, and mediates immune homeostasis.
IMMUNE HOMEOSTASIS: the balance between opposing pro-inflammatory and anti-inflammatory processes.
For homeostasis and the continued viability of the host, there must be both resolution of the challenge to the tissues as well as healing.
Healing, besides replacing the injured area with tissue, also implies successfully dealing with damaging agents and then reining in the inflammatory response that could itself damage tissue further.
Therefore, healing is part of the inflammation continuum:
- Recognize a threat or damage with "sentinel" cells of the innate immune system.
- Launch immediate response via the innate immune system (Inflammation), including complement, which
- identifies foreign material or damaged self (opsonization--the process of coating of targets with complement molecules to promote their elimination);
- eliminates targets via adherence followed by phagocytosis; and
- promotes inflammatory and immune responses to targets.
Complement activates the inflammatory and immune responses, leading to vasodilation, activation of other cell types, the release of mediators (histamine from mast cells), and initiates chemotaxis of other cells.
- Begin the cascade of adaptive immunity as insurance for the future. "Fool me once..." (Adaptive Immune System)
- Initiate anti-inflammatory measures to balance the inflammatory response to just what's needed for the threat or damage.
- Begin moving in cellular components to replace, restrengthen, or regenerate the damaged areas: Healing.
The above are not discrete steps, but a progression that includes considerable overlap. Even while fighting antigenic bacteria or viruses, already there are healing steps beginning in the background. As such, repair (healing) is actually a part of the inflammatory process, since it involves the activation of keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets, the organized cell migration and recruitment of endothelial cells for blood vessel development, and the coordination of many growth factors and cytokines.
(Cytokines can be both pro-inflammatory and anti-inflammatory--[SEE BELOW].)
Pro-inflammatory vs. Anti-inflammatory
Although the processes of inflammation are an important protective mechanism used by the body to deal with potentially damaging agents, these processes themselves are potentially damaging to the body and must be closely regulated.
The basic steps in acute inflammation allow white blood cells to move from the blood to the tissue location where they are required. Acute inflammation can resolve completely if the inciting agent is removed, or it can have one of several other sequelae, including chronic inflammation (impaired healing). In cases where inflammation continues, it becomes important to control inflammation with anti-inflammation measures to protect the body.
To prevent uncontrolled inflammation, there are active homeostatic processes within the innate immune system that regulate and limit inflammatory responses.
- Macrophages, besides playing a crucial role in host defense, also suppress dendritic cell maturation and antigen presentation, and they release anti-inflammatory mediators which dampen the inflammatory macrophage and dendritic cell functions. They produce prostaglandins which inhibit inflammatory functions of macrophages and T-cells.
- A subtype of neutrophil promotes vascularization; another subtype inhibits T-cell responses.
- Prostaglandins--inhibit cytokine activity and macro functions of macrophages.
- Cytokines, which can be pro-inflammatory (via a positive feedback loop) or anti-inflammatory (via a negative feedback loop), are an important part of the homeostatic balance. Depending on from which cells they originate, they balance the inflammatory response in various ways:
Pro-inflammatory cytokines: induce fever, other cytokines, and T-cell stimulation; increases T-cell proliferation and activates B-cells; increase IgE; inhibit apoptosis; activate neutrophils, T-cells, natural killer cells, and macrophages; promote chemotaxis for monocytes and T-cells..
Anti-inflammatory cytokines: suppress delayed-type hypersensitivity, decrease the production of pro-inflammatory cytokines; promote fibroblast proliferation, angiogenesis, and collagen synthesis; decrease T-cell proliferation.
Once hemostasis is achieved, healing is in an orderly and efficient manner of overlapping phases that include inflammation, epithelialization, fibroplasia, and maturation:
REGENERATION: occurs when the necrotic cells are replaced by new cells that form similar tissue as was originally there.
Epithelialization: (AKA "migration") is basal cell proliferation and epithelial cell migration occurring in the fibrin bridgework inside a clot. Proliferation continues until individual cells are surrounded by cells of similar type. Migration ceases when the layer is rejuvenated.
Fibroplasia: fibroblast proliferation, accumulation of ground substance, and collagen production.
Fibroblasts arrive at the site of injury within 24 hours (long before the inflammatory phase is completed) and synthesize collagen, the primary structural protein of the body. Collagen is secreted as an amorphous gel that strengthens over time by developing a collagen matrix, which in turn stimulates angiogenesis. Granulation tissue is the result of the combined production of collagen and growth of capillaries.
Maturation: when the levels of collagen production and degradation equalize and tensile strength starts to increase over time. Eventually, capillaries disappear from the area by apoptosis and the scar loses its red color.
The tensile strength of the wound is directly proportional to the amount of collagen present, via collagen cross-linking and collagen remodeling.
The complex overlap of the healing pathway prevents a single primary factor from disrupting the process such that impaired healing usually occurs in the setting of multiple, smaller contributing issues to stall the healing process; however, infection or ischemia alone can impair wound healing.
Repair: occurs when injured tissue is replaced with scar tissue.
Debridement: when dead tissue is removed or excised from a wound.
Primary intention: the healing of a clean wound without tissue loss.
Secondary intention: the healing of a wound when primary intention is not possible; the wound “granulates” and takes longer to heal and may need wound care and intentional debridement.
Dehiscence: separation of reapproximated edges of a wound after previous closure.
In the abdomen, the fascia is the main supportive layer keeping the abdominal contents inside the abdomen. If a complication of surgery includes a fascial wound dehiscence, abdominal organs (intestines, omentum, etc.) literally can fall out of a patient, creating a life-threatening surgical emergency.
A sign of impending dehiscence of an abdominal wound is seeing serosanguinous fluid leaking through a suture line or a wound that appears closed. This implies leakage of fluid from the abdomen, blood-tinged, and requires immediate rapid transport and abdominal binding en route.
Dysfunctional wound healing can be a direct reflection of dysfunction during the inflammation process, and dysfunction during the reconstruction phase (impaired collagen synthesis or epithelialization, wound disruption, or impaired contraction of vessels).
IN NEONATES: Neonates have transiently depressed inflammatory and immune functions and express complement deficiency; neutrophils are not capable of efficient chemotaxis and are deficient in collectins and collectin-like proteins.
IN THE ELDERLY: The elderly population's self-defense mechanisms are less than favorable as well. Impaired inflammation is likely a result of chronic illness. Medication taken over years may decrease the response of the inflammatory system, the regenerative ability of the skin makes healing wounds slower, and infections are more common in the elderly population.
In the Field
In the field, your most likely encounter with the phenomena of inflammation and healing are complications of surgical, traumatic, or infectious wounds, including
- sudden wound dehiscence (separation),
- abscess formations,
- sepsis, and
For these, transport with support of ABC (airway, breathing, and circulation), pain management, and emotional support are necessary.
►Call to Action: TRANSPORT
A sign of pending dehiscence is noting serosanguinous fluid leaking from an otherwise closed wound. Supine position en route to an appropriate (surgical) hospital with an abdominal binder if possible is the best option to keep such a patient stable.