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Inflammation and Repair


Inflammation is a tightly controlled, rapid, scalable response by the body to pathogens and injury. It is a protective response by the body to ensure removal of detrimental stimuli and serves to initiate a healing process for repairing damaged tissue1,2 It is controlled at a cellular and molecular level and is an innate response to injury or infection. Classically there are five cardinal signs of inflammation:

·        Dolor (pain)

·        Calor (heat)

·        Rubor (redness)

·        Tumor (swelling)

·        Functiolaesa (loss of function)

Overview of the Inflammatory Response

The process of acute inflammation is initiated by macrophages, dendritic cells, histiocytes, Kupffer cells, and mastocytes in response to an injury or infection. These cells have receptors on their surface known as Pattern Recognition Receptors (PRRs) which recognize molecules that are shared by pathogens but distinct from host molecules, collectively referred to as Pathogen-Associated Molecular Patterns (PAMPs), as well as endogenous molecules released from damaged cells, termed Damage-Associated Molecular Patterns (DAMPs).2 At the onset of an infection or other injury these cells undergo activation (one of their PRRs recognizes a PAMP or DAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Increased blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels results in an exudation of plasma proteins and fluid into the tissue causing swelling (tumor). Some of the released mediators such as bradykinin increase the sensitivity to pain (dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils, outside of the blood vessels (extravasation) into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury. The loss of function (functio laesa) is related to swelling and pain.

In addition to cell-derived mediators, several biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis. Inflammatory mediators have short half lives and are quickly broken down in the tissue and acute inflammation ceases once the stimulus has been removed.

Causes of Inflammation

The causes of inflammation may be broadly characterized as infection, trauma, burns, irritants, and immune system dysfunction. Infection is not synonymous with inflammation, as one can have infection without inflammation and inflammation without infection. Examples would include cellulitis, tonsillitis, and periodontitis. Trauma, especially blunt-force trauma, is associated with redness and swelling at the site of injury in addition to any bruising that may occur. Burns manifest all five cardinal signs of inflammation depending on the severity of the burn. Irritants include chemical, thermal, and mechanical irritation, and also chronic or intermittent hypoxia and tissue ischemia.3 Immune system dysfunction includes a broad category of conditions such as autoimmune disorders, HIV, agranulocytosis, and immunoglobulin deficiencies.

Types of Inflammation

Acute and chronic inflammation share many features but tend to have different cellular and molecular patterns. Acute inflammation is a short-term process, usually appearing within minutes to hours and resolving quickly upon removal of the irritant. (See Figure 1.) Granulomatous inflammation involves the development of cellular whorls consisting of collagen and dead cells, and includes conditions such as tuberculosis, leprosy, sarcoidosis, and syphilis. (See Figure 2.) In fibrinous inflammation, a large increase in vascular permeability allows fibrin to pass into tissues resulting in a fibrinous exudate. This is most commonly seen in serous cavities as seen in fibrinous pericarditis. (See Figure 3.) Purulent inflammation is a common pattern where a cavity forms filled with pus containing large numbers of dead leukocytes, tissue cells, and fluid. This is particularly seen with certain bacterial pathogens, especially Staphylococcus aureus. (See Figure 4.) Another form of acute inflammation is serous inflammation which results in accumulations of watery fluid. Skin blisters and bullae are examples. (See Figure 5.) Ulcerative inflammation results in the development of necrotic tissue with ulceration exposing lower skin layers. This can be seen in aphthous ulcers and certain viral infections such as herpes simplex. (See Figure 6.)

Chronic inflammation consists of the simultaneous destruction of tissues from inflammatory mediators and repair of those tissues. This is a persistent acute inflammation due to non-degradable pathogens, viral infection, persistent foreign bodies, or autoimmune reactions. Because of the associated tissue destruction, significant damage can occur to the tissue. Chronic periodontitis would be one example.

Components of the Inflammatory Response

To date nearly 100 chemical mediators associated with inflammation have been defined. The stimulation of PRRs results in the transcriptional activation of inflammatory mediators2, upregulating the genes responsible for producing proinflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6. These cytokines regulate the cell death of inflammatory tissues, modify vascular endothelial permeability, recruit white blood cells to inflamed tissues, and induce the production of acute-phase proteins. Plasma-derived mediators become activated including bradykinin, complement components, and clotting factors. Several components of the complement family bind together to form a membrane attack complex (MAC) which when activated is able to pierce bacterial walls and cause bacterial death. The MAC forms trans-membrane channels and disrupts the phospholipid bilayer of the bacteria. Cell-derived mediators include lysosome granules, histamine, interferon-γ, interleukins, leukotrienes, nitric oxide, prostaglandins, and tumor necrosis factor. These mediators work together to cause vasodilation and provide a chemotactic gradient for macrophages and neutrophils leading them to the source of irritation. At the same time, anti-inflammatory mediators are produced to keep the entire process under control.

Inflammation results in numerous local and systemic hemodynamic changes. Localized vasodilation mediated by histamine, nitric oxide, bradykinin, and prostaglandins causes the redness and heat seen in acute inflammation. Arteriolar endothelium is affected, leading to increased porosity of arterioles and allowing extravasation of cells, fluid, and antibodies. Over time the increased extracellular fluid is pulled away by the lymphatic system to local lymph nodes for further processing of pathogens. Large areas of inflammation can cause shunting of significant quantities of intracellular fluid into non-vascular tissue space, causing intravascular depletion, hypovolemia, renal failure, and shock, a syndrome referred to as “third-spacing”. Early signs of hypovolemia include hypotension, tachycardia, lethargy, and decreased urine output.

Dramatic cellular changes occur in inflammation. The acute phase is characterized primarily by a leukocyte response, although other cells increase as well. Lymphocytes known as “natural killer” or NK cells act quickly with T- and B-lymphocytes in response to infection, especially viral infections. The bone marrow responds to inflammation by producing larger numbers of neutrophils and lymphocytes, often releasing cells before they are mature. In general, bacterial infections stimulate neutrophilia and leukocytosis while viral infections are often associated with lymphocytosis and sometimes leukopenia. As the irritant is removed, the reactive cells are removed by apoptosis. If inflammation persists, the types of cells present change over time to include larger numbers of mononuclear cells and fibroblasts. Local monocytes are transformed into macrophages and dendritic cells to more aggressively attack pathogen.4 These cells are not as selective as granulocytes and cause considerable collateral damage to surrounding tissues. (See Figure 7.)


Systemic Response

If the focus of inflammation is localized, there may be little or no significant systemic response. Fever often develops and is the result of release of bradykinins and prostaglandins into the blood stream. Leukocytosis is a bone marrow response to inflammation, and in general the degree of leukocytosis correlates to extent of local insult. As inflammation increases, there is often hyperglycemia resulting from increased insulin resistance.5 With the extravasation of fluid and resultant hypovolemia, the patient may experience hypotension, tachycardia, lethargy, renal failure, respiratory failure, coma, and even death. In severe systemic responses, patients can develop the Systemic Inflammatory Response Syndrome which is a type of a cytokine storm where cytokines stimulate T-cells to produce more cytokines, resulting in cytokine over-production and severe systemic reactions, multisystem organ failure, and death.

Regeneration and Repair

Resolution of inflammation can be rapid or prolonged. There are four common types of healing, and combinations of these types occur as well. With complete resolution, once the irritant is completely removed the reactive white blood cells die by apoptosis and autophagy6, cytokines and other chemical mediators break down quickly owing to their short half-lives, anti-inflammatory enzymes are produced, and extra fluid is removed by the lymphatic system. Damaged parenchymal cells regenerate and tissues return to normal. When there has been more extensive damage to tissues or the damage occurred in tissues that cannot regenerate, resolution results in scar formation and fibrosis. Some inflammatory conditions result in abscess formation, the tissue's attempt to wall off the infection to contain it. This cavity is difficult for the tissue to resolve because of its poor internal vascularity, typically requiring surgical intervention. Another potential outcome of acute inflammation is chronic inflammation in which the injurious agent is not completely removed, stimulating a continuous process of tissue destruction and regeneration. Chronic foci of inflammation typically show a predominance of macrophages containing powerful destructive enzymes, and systemic markers of inflammation increase. Chronic inflammation has been associated with a higher risk of systemic illnesses such as atherosclerosis7, cancer8, and depression9.

The changes on a cellular basis with resolution of inflammation are rapid and profound. With resolution, the number of activated lymphocytes and neutrophils falls locally and systemically through apoptosis. The total intravascular white blood cell count falls with fewer immature white blood cells seen on the peripheral smear.

Implications for Wound Healing

All wounds by definition have a component of inflammation. The factors that influence resolution of inflammation also influence wound healing. The body’s response to infection or injury is more rapid in tissues with excellent blood supply, and more rapid response to injury correlates with better resolution of inflammation and better healing. In converse, poorly vascular tissues are less likely to resolve inflammation without residual damage. Older patients and patients with underlying diseases such as diabetes are also less likely to heal well due to poor vascularization of tissues. (See Figure 8.) If infection or irritation persists (such as in chronic periodontitis), there is more scarring and poor wound healing. In addition, wounds that are not meticulously cleaned are likely to have included bacteria and debris, inciting chronic inflammation and poor wound healing.

Wounds heal by building fibrotic bridges and scars in an attempt to rebuild tissue integrity. The most significant factors that affect cutaneous wound healing include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition.10 Scars are minimized by primary closure using inert suture material, good wound edge approximation, and sterile technique. Scars contract in size over time, and can result in traction deformities of tissues as well as compression of underlying structures. Overproduction of collagen leads to hypertrophic scars and keloids.

Inflammation and repair are highly complex, locally-controlled processes that require the interplay between cellular- and plasma-derived factors. Tissues produce both pro-inflammatory and anti-inflammatory peptides to keep the process in check and appropriately scaled to the size of the insult. An understanding of the variables involved in the resolution of inflammation can help the surgical professional gain a better understanding of chronic inflammation and surgical wound healing.


1.            Medzhitov R. Origin and physiological roles of inflammation. Nature. Jul 24 2008;454(7203):428-435.

2.            Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. Mar 19 2010;140(6):805-820.

3.            Schwartz RS, Eltzschig HK, Carmeliet P. Hypoxia and inflammation. New England Journal of Medicine. 2011;364(7):656-665.

4.            Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. Nov 2011;11(11):762-774.

5.            Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-246.

6.            Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. Jan 20 2011;469(7330):323-335.

7.            Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. Sep 2012;32(9):2045-2051.

8.            Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biology and Medicine. 2010;49(11):1603-1616.

9.            Vogelzangs N, Duivis HE, Beekman AT, et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012;2(2):e79.

10.         Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. Mar 2010;89(3):219-229.

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