Inflammation and Repair
THE NEXTDDS
Introduction
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.
References
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antidepressant medication with inflammation. Transl Psychiatry. 2012;2(2):e79.
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Dipietro LA. Factors affecting wound healing. J Dent Res. Mar 2010;89(3):219-229.