Notes on Inflammatory Response

• Inflammatory response is a complex process that involves vascular and cellular changes, and may also include systemic changes.

• The process is initiated by tissue damage or infection, and is aimed at eliminating the cause of injury and promoting healing.

• The response is characterized by the release of chemical mediators such as histamine, prostaglandins, and cytokines that cause vasodilation and increased vascular permeability.

• This leads to the migration of white blood cells (WBCs) to the site of injury, where they phagocytose and destroy invading pathogens or damaged tissue.

• The inflammatory response is most efficient when it rids the body of injury, enhances healing processes, and resolves.

• However, in some disorders such as rheumatoid arthritis (RA), tuberculosis (TB), and atherosclerosis, inflammation can persist and ultimately cause unremitting damaging effects on the body; these are considered chronic inflammatory conditions.

• Chronic inflammation is characterized by the infiltration of immune cells, tissue destruction, and the formation of scar tissue.

• Chronic inflammation can lead to tissue damage, organ dysfunction, and an increased risk of developing other diseases such as cancer and cardiovascular disease.

Types of Inflammation

Acute Inflammation

• Rapid onset

• Reaction to cell injury

• Rids body of offending agent

• Enhances healing

• Terminates after a short period

  • Hours

  • Few days

Chronic Inflammation

• Inhibits healing

• Causes continual cellular damage

• Organ dysfunction

• Inflammatory reaction persists

Acute Inflammation

Mind Map: Acute Inflammation

Types of Injurious Stimuli

• Infections

• Microbial Toxins

• Physical Injury

• Surgery

• Cancer

• Chemical Agents

• Tissue Necrosis

• Foreign Bodies

• Immune Reactions

Three Main Stages of Acute Inflammation

1. Vascular Permeability

2. Cellular Chemotaxis

3. Systemic Responses

Vascular Permeability

• Inflammatory mediators cause blood vessels to dilate and become more permeable

• Allows fluids, WBCs, and platelets to travel to site of injury or infection

• Vasodilation of arterioles followed by enhanced capillary permeability

• Increased fluid in tissues dilutes toxins and lowers pH to inhibit microbial growth

• Five Cardinal Signs of Inflammation:

  • Rubor (redness)

  • Tumor (swelling)

  • Calor (heat)

  • Dolor (pain)

  • Loss of function (function laesa)

• Fluid leaving capillaries is protein-rich filtrate of blood containing WBCs

• WBCs perform defensive activities, causing edema or swelling

• Purulent exudate is fluid rich in protein from WBCs, microbial organisms, and cellular debris

• Transudate is fluid containing little protein and mainly watery filtrate of blood

• Effusion is accumulation of fluid in body cavity due to inflammatory or non-inflammatory processes

Cellular Chemotaxis

• WBCs migrate to site of injury or infection

• Attracted by chemotactic factors released by injured cells, WBCs, and plasma proteins

• WBCs phagocytize and digest microbes and cellular debris

Systemic Responses

• Inflammatory mediators released into bloodstream, causing systemic effects

• Fever, leukocytosis, increased plasma protein synthesis, malaise, fatigue, and muscle catabolism

• Systemic effects help prevent spread of infection and promote healing

Mind Map: Leukocytosis

Central Idea

Leukocytosis is the increased number of WBCs in the bloodstream during inflammation.

Main Branches

• Cellular Phase of Inflammation

• Leukemoid Reaction

• Genetic Disorders

• Types of WBCs in Inflammatory Infiltrate

• Infections and Leukopenia

• Inflammatory Mediators

Cellular Phase of Inflammation

• Chemical signal attracts platelets and WBCs to site of injury

• Leukocytosis: increased number of WBCs released from bone marrow into bloodstream

• WBC count can determine severity of infectious process

• Margination: WBCs line up along endothelium in area of inflammation

• Adhesion: WBCs adhere to endothelial lining of blood vessels

Leukemoid Reaction

• Extreme elevation in number of WBCs

• Can occur in conditions such as leukemia

Genetic Disorders

• Deficiency in selectins and integrins can lead to immunodeficiency and increased risk of infection

Types of WBCs in Inflammatory Infiltrate

• Neutrophils predominate during first 6 to 24 hours

• Monocytes replace neutrophils and change into macrophages over next 24 to 48 hours

• Macrophages are predominate type of WBC in persistent inflammatory reactions

• Exceptions to this pattern: neutrophils dominate in certain infections, lymphocytes dominate in viral infections, eosinophils dominate in allergic reactions

Infections and Leukopenia

• Some infections cause decreased number of WBCs (leukopenia)

• Examples: typhoid fever, infections caused by rickettsia, protozoa, and viruses

Inflammatory Mediators

• WBCs and injured tissue release many different inflammatory mediators

• Some amplify the inflammatory process, recruiting more WBCs to the area of injury

• Others attempt to stop the inflammatory process

Mediators of Inflammation

• Definition: Substances that promote or inhibit inflammatory reactions

• Anti-inflammatory pharmaceutical agents have been devised to counteract different types of promoting mediators

• Types of mediators: interleukins, tumor necrosis factor alpha, cytokines, chemokines, and acute phase proteins

Cytokines, Chemokines, and Acute Phase Proteins

• Cytokines: Modulate the inflammatory reaction by amplifying or deactivating the process; cause localized and systemic effects

• Chemokines: Proteins that attract leukocytes to the endothelium at the area of injury

• Acute phase proteins: Facilitate WBC phagocytosis of microbes and other foreign material; assist in the analysis of the inflammation process occurring in the body

• Examples of acute phase proteins: C-reactive protein (CRP), fibrinogen, serum amyloid A, and hepcidin

White Blood Cells (WBCs)

• Five basic types of WBCs: neutrophils, lymphocytes, eosinophils, basophils, and monocytes

• Neutrophils: Also referred to as polymorphonuclear leukocytes (PMNs); involved in phagocytosis of microbial organisms and cellular debris

• Granulocytes: Neutrophils, basophils, and eosinophils; contain important enzymes and anti-microbial proteins that support the inflammatory process and fight infection

• Respiratory burst: Releases free radicals that disrupt microbial membranes, leading to their destruction

• Chronic granulomatous disease: Causes a deficiency of free radicals, leading to immunodeficiency and increased risk of infections

1. Persons enduring acute inflammation experience symptoms throughout the whole body, such as fever, pain, lymphadenopathy, anorexia, sleepiness, lethargy, anemia, and weight loss

Systemic Responses

• Inflammatory mediators responsible for many of these systemic effects: prostaglandins (PGs), TNF-alpha, and ILs

• Frailty: Inflammatory mediators are elevated in older adults suffering from frailty

Fever

• Increase in body temperature; common manifestation of inflammation and infection

• Pyrogens: Substances that cause fever; activate PGs to reset the hypothalamic temperature-regulating center in the brain to a higher level

• Higher body temperature increases the efficiency

Outcomes of Acute Inflammation

Acute inflammation is a short-lived reaction that eliminates an injurious agent, allows little tissue destruction, and terminates by facilitating the regeneration of normal tissue. There are three possible outcomes of acute inflammation:

1. Complete resolution: Ideally, acute inflammation results in complete resolution, which involves normalization of vascular permeability, deactivation of chemical mediators, elimination of cellular debris and edema, and apoptosis of WBCs.

2. Healing by connective tissue: At times, severe tissue injury and a large acute inflammatory reaction preclude the regeneration of normal cells. In such cases, resolution and healing occur through the proliferation of connective tissue. Cellular debris and exudates are reabsorbed, and fibrous scar tissue replaces damaged cells.

3. Chronic, persistent inflammation: Finally, there are times when acute inflammation cannot be resolved because of persistence of the injurious agent or other interference with healing. In these cases, inflammation becomes a chronic, persistent condition with failure to resolve and extensive tissue damage.

Chronic Inflammation

An inflammatory reaction that persists for a prolonged time, from weeks to months, without resolution or healing is considered a chronic inflammatory disorder. Chronic inflammation is characterized by the predominance of monocytes, lymphocytes, and macrophages, and is caused by specific etiologic agents or unknown reasons.

Etiologies of Chronic Inflammation

Causes of chronic inflammation include:

• Persistent infection by microorganisms that are difficult to eradicate (e.g., TB).

• Hypersensitivity disorders, which cause excessive activation of the immune system. Examples of these disorders include autoimmune diseases such as RA, multiple sclerosis (MS), or systemic lupus erythematosus (SLE).

• Prolonged exposure to potentially toxic agents such as coal dust, which causes anthracosis (black lung).

• Atherosclerosis, a chronic inflammatory disease affecting the arterial wall that is caused by agents that damage the endothelial cells.

• Some cancers, such as basal cell carcinoma, are promoted by chronic inflammatory reactions.

T and B lymphocytes commonly amplify and perpetuate chronic inflammation. These are the cells found in chronic autoimmune disorders. Chronic inflammation often causes a distinctive histological pattern of granulomatous changes. A granuloma is an area where macrophages have aggregated and are transformed into epithelial-like or epithelioid cells. The epithelioid cells are surrounded by lymphocytes, fib

Tissue Repair and Wound Healing

Tissue healing and regeneration are desirable outcomes of cell injury and inflammation. The process of wound healing can be divided into four phases: Hemostasis, Inflammation, Proliferation, and Remodeling.

Normal Wound Healing

• Hemostasis occurs after injury as exposed collagen surfaces attract platelets. Platelets aggregate and secrete inflammatory mediators such as serotonin, histamine, and platelet-derived growth factor.

• Inflammation occurs next in the acute phase, after injury. Vasodilation, increased vascular permeability, and chemotaxis occur during this phase.

• In the subsequent proliferation phase, granulation tissue forms. The fibroblast is the key cell involved in this process. Vascular endothelial cells create new blood vessels in a process called angiogenesis.

• The remodeling phase begins approximately 3 weeks after injury, where the scar tissue is structurally refined and reshaped by fibroblasts and myofibroblasts.

Primary, Secondary, and Tertiary Intention Wound Healing

Primary Intention

• Best exemplified by healing of a clean, surgical laceration.

• Requires predominately surface re-epithelialization and re-establishment of tissue integrity of the approximated edges.

Secondary Intention

• Healing begins when there is extensive loss of tissue within a wound.

• Regeneration of the same cells to replace lost tissue is not possible.

• Abundant granulation and fibrous tissue are necessary to fill the defect and restore the original structure of tissue.

• Inflammation process within this type of wound is more intense and longer in duration.

• Wound contraction occurs because of myofibroblasts, which are connective tissue cells with smooth muscle characteristics.

• Substantial scar formation and thinning of the epidermis occurs.

• Highly susceptible to infection, complications, and deformity.

Tertiary Intention

• The wound is missing a large amount of deep tissue and is contaminated.

• It is cleaned and left open for 4 to 5 days before closure.

• The wound may require temporary packing with sterile gauze and have extensive drainage that often requires insertion of a drainage tube.

• By the fifth day, WBC phagocytosis of contaminated tissues occurs and the processes of epithelialization, collagen deposition, and maturation take place.

• Foreign materials are walled off by macrophages and other types of leukocytes to form granulomas.

• There is prominent scarring with healing.

• This type of wound commonly requires a skin graft.

Pressure Ulcers and Severe Burns

• Pressure ulcers and severe burns are examples of wounds that require secondary and tertiary intention healing.

• These wounds have large areas of missing skin, dermis, and deeper tissue, which are replaced by scar tissue.

• Primary, secondary, and tertiary intention wounds do not regain full tensile strength of unwounded skin after healing is completed.

• Clinicians and patients need to be aware of the weakened integrity of the skin and underlying tissues.

• Careful support of the area to facilitate healing is necessary during the first few weeks after surgery.

• After sutures are removed, usually 1 to 2 weeks later, wounded skin is again in a vulnerable, weakened state.

• The healed wound builds to a maximal tensile strength of 70% to 80% after 3 months.

• Some wounds develop eschar tissue.

• Eschar is dead tissue that sheds or falls off from healthy skin.

• It is common in burn wounds and pressure ulcers.

• Eschar is typically tan, brown, or black and often has a crusty top layer.

Notes on Wound Healing

• Wounds that require secondary and tertiary intention healing have large areas of missing skin, dermis, and deeper tissue, which are replaced by scar tissue.

• Primary, secondary, and tertiary intention wounds do not regain full tensile strength of unwounded skin after healing is completed.

• Clinicians and patients need to be aware of the weakened integrity of the skin and underlying tissues.

• Careful support of the area to facilitate healing is necessary during the first few weeks after surgery.

• After sutures are removed, usually 1 to 2 weeks later, the wound still needs to be protected and supported until it regains its full strength.

• Pressure ulcers and severe burns are examples of wounds that require secondary and tertiary intention healing.

• Scar tissue is not as strong as the original tissue, and it may be more prone to injury and tearing.

• Patients should be advised to avoid activities that may put stress on the healing wound.

• Proper wound care and follow-up appointments with the clinician are important to ensure proper healing and to monitor for any complications.

  Factors That Affect Wound Healing

  Wound healing is a complex process that involves many body systems. The following factors affect wound healing:

  • Nutrition: Lack of adequate nutrients, particularly protein, decreases cellular regeneration and metabolic function. Protein is necessary for cellular regeneration and synthesis of connective tissue. Carbohydrates can be used for energy in order to spare protein sources for tissue healing. Fats are essential components of cell membranes that are synthesized during the healing process. Most vitamins are essential co-factors for the body’s metabolic activities. They are particularly important in wound healing. For wounds to heal, a patient must be in a state of positive nitrogen balance. Nitrogen balance is defined as the difference between nitrogen intake and nitrogen excretion. Protein is the best source of nitrogen in the diet.

  • Oxygenation: Oxygen is needed for neutrophil phagocytosis and collagen synthesis.

  • Circulation: Lack of adequate circulation predisposes the individual to ischemia, infarction, and consequent infection of necrotic tissue, also known as gangrene.

  • Immune strength: Diabetes, corticosteroid use, cancer, HIV, aging, and immunosuppressant agents diminish WBC activity, delay wound healing, and predispose to infection.

  • Contamination: Foreign bodies present in a wound diminish healing ability and predispose to infection. Foreign bodies include sutures that remain in place too long, surgically inserted devices such as pacemakers, heart valves, and orthopedic or prosthetic implants.

  • Mechanical factors: Includes increased localized pressure, torsion, and excessive fat tissue.

  • Age: The regeneration process of infants and young children is superior to that of adults. Studies show that fetal wounds heal without fibrosis or scarring. Elderly adults have the slowest healing process.

Blood Flow and Oxygen Delivery

• Arterial and venous circulation should be optimal in the region that requires healing.

• Healing tissue needs a rich supply of nutrients and oxygen delivered via arterial blood flow.

• Adequate waste removal provided by efficient venous flow is necessary.

• Bacteria, cellular debris, necrotic tissue, and local toxins need to be eliminated as tissue regenerates.

• Wounds that attempt to heal under ischemic conditions require lengthier periods and are susceptible to infection.

• Ischemia fosters the growth of anaerobic bacteria such as Clostridium perfringens, the microorganism that causes gangrene.

• Obesity tends to impair wound healing because adipose tissue is less vascular and, in turn, deficient in oxygen.

• Gangrene occurs when ischemic tissue undergoes bacterial infection leading to tissue necrosis.

• Brisk arterial blood flow is needed to deliver maximal oxygen to the area.

• Oxygen facilitates collagen synthesis and WBC function.

• Without oxygen, WBCs cannot kill phagocytosed microorganisms and collagen growth is deficient.

• Hyperbaric oxygen facilitates collagen synthesis, angiogenesis, neutrophil phagocytic activity, and fibroblast proliferation.

• Smoking has a deleterious effect on wound healing.

• Nicotine in cigarettes acts as a vasoconstrictor, which decreases circulation and subsequent oxygenation.

• The smoke also contains free radicals, which are oxidizing agents that damage cell membranes.

Immune Strength

• Optimal wound healing requires a strong immune system capable of eliminating dead tissue, walling off foreign matter, and killing microorganisms.

• A brisk inflammatory response is needed in the initial stages of tissue injury, followed by efficient phagocytic WBC function and strong acquired immune reactions.

• Immunocompetent children have more efficient healing processes than adults.

• Fetal wounds heal without fibrosis or scarring, and are richer in hyaluronic acid, a component thought to facilitate cellular regeneration and collagen synthesis.

• Older patients heal less efficiently because of aged skin, a thinned dermal layer, reduced collagen and fibroblast synthesis, and greater potential for secondary conditions that reduce blood flow to the area.

• Conditions that cause immunosuppression, such as cancer, HIV, diabetes mellitus, and corticosteroid use, may delay healing.

• Diabetes mellitus decreases the phagocytic ability of neutrophils and macrophages, which hinders the inflammation response in wound healing.

• Corticosteroids suppress the inflammation phase of wound healing and inhibit collagen synthesis, which is integral to the proliferative and remodeling phases of wound healing.

• Infection is the single most important cause of delayed healing, and a wound's susceptibility to infection is influenced by the patient's immune strength, the type of wound present, and conditions of injury.

• Vigorous irrigation, cleansing, and removal of necrotic tissue and foreign matter are necessary to facilitate optimal wound healing.

Foreign Bodies

• Fragments or debris left inside the wound due to traumatic injury can impede healing.

• Examples include bullets, glass, steel, wood, or bone.

• Sutures can act as foreign bodies if they are not removed in a timely manner from the healing wound site.

• Surgically inserted devices such as pacemakers, heart valves, and orthopedic or prosthetic implants can become sources of infection.

• They can predispose the patient to sepsis.

Mechanical Factors

Mechanical factors can affect wound healing in various ways. Here are some important points to consider:

• Increased localized pressure, torsion, or excessive fat tissue can cause wound dehiscence.

• Adipose tissue is difficult to close surgically, and surgical procedures on obese patients require more time and cause more tissue trauma.

• In addition, surgical wound closure is more difficult in obese patients because of the tension on the sutures.

• The abdomen is a surgical site where sutured wounds need support.

• The patient should be taught how to splint the surgical site during coughing or movement.

Dysfunctional Wound Healing

Factors that can lead to dysfunctional wound healing include:

1. Malnutrition: Protein, vitamins, and minerals are essential for wound healing. A lack of these nutrients can lead to delayed healing or wound dehiscence.

2. Infection: Infection can delay healing and lead to chronic wounds. Bacteria can also cause tissue damage and interfere with the healing process.

3. Poor blood supply: Adequate blood flow is necessary for wound healing. Poor circulation can lead to delayed healing or tissue death.

4. Chronic diseases: Chronic diseases such as diabetes and peripheral vascular disease can impair wound healing.

5. Medications: Certain medications, such as corticosteroids and chemotherapy drugs, can impair wound healing.

6. Mechanical stress: Excessive mechanical stress on a wound can delay healing or cause dehiscence.

7. Age: Aging can impair wound healing due to decreased collagen production and decreased immune function.

Complications of dysfunctional wound healing include:

1. Chronic wounds: Wounds that do not heal within 4-6 weeks are considered chronic wounds. These wounds can lead to infection, tissue damage, and amputation.

2. Dehiscence: Dehiscence is the separation of the edges of a wound. This can occur due to poor wound closure or excessive mechanical stress on the wound.

3. Hypertrophic scars: Hypertrophic scars are raised, red scars that do not extend beyond the boundaries of the original wound. These scars can be itchy and painful.

4. Keloids: Keloids are raised, red scars that extend beyond the boundaries of the original wound. Keloids can be itchy and painful and may require surgical removal.

5. Contractures: Contractures occur when the skin and underlying tissues become tight and restrict movement. Contractures can occur after burns or other injuries.

Prevention of dysfunctional wound healing includes:

1. Proper nutrition: Adequate protein, vitamins, and minerals are essential for wound healing.

2. Infection control: Proper wound care and antibiotic therapy can prevent infection.

3. Adequate blood supply: Proper circulation can

Wound Rupture

• Most wounds require structural support and immobility for initial healing period.

• Undue tension on the wound can inhibit the approximation of edges and epithelialization of the surface.

• High tension on the edges of abdominal wall wounds due to mechanical stresses of coughing, vomiting, and the Valsalva maneuver.

• Previously closed wound edges open and rupture is called wound dehiscence.

• In rare cases, internal tissues and organs can extrude from the open wound, a condition called wound evisceration.

• Abdominal wounds are most susceptible to these conditions.

Possible Complications of Wound Healing

Wound healing is a complex process that involves several stages. However, sometimes the healing process can be disrupted, leading to complications. Some of the possible complications of wound healing are:

1. Keloid: It is the hyperplasia of scar tissue that extends beyond the boundaries of the original wound.

2. Contractures: It is the inflexible shrinkage of wound tissue that pulls the edges towards the center of the wound, leading to limited mobility.

3. Dehiscence: It is the opening of a wound's suture line, which can cause bleeding and infection.

4. Evisceration: It is the opening of a wound with extrusion of tissue and organs, which can be life-threatening.

5. Stricture: It is the abnormal narrowing of a tubular body passage due to the formation of scar tissue, which can cause difficulty in swallowing or breathing.

6. Fistula: It is the abnormal connection between two epithelium-lined organs or vessels that normally do not connect, which can cause infection and inflammation.

7. Adhesions: It is the internal scar tissue between tissues or organs, which can cause pain and discomfort.

It is essential to take proper care of the wound to prevent these complications. In case of any complications, seek medical attention immediately.

Keloid Formation

• Wound healing can be complicated by hyperplastic epithelialization and collagen formation.

• Excessive accumulation of epithelium and collagen can form a hypertrophic scar, also called a keloid.

• Keloid formation is more common in persons of African descent.

• The etiology of keloid formation is unknown.

• Keloids can be reduced by cosmetic surgery.

Notes on Contractures and Strictures

• Wound contraction is the final stage of second intention healing.

• Exaggerated wound contraction can lead to a deformity called a contracture.

• Contractures are inflexible shrinkages of wound tissue that pull the edges toward the center of the wound.

• Burn wounds are particularly prone to contractures, which can limit mobility across a joint surface.

• Strictures are another type of wound complication that causes narrowing or closure of an open area of the body.

• Scar tissue is the primary cause of strictures, which can occur in ducts, canals, or tubes.

• For example, strictures in the esophagus can narrow or completely close off the passage of food.

• Contractures and strictures can be prevented or minimized with proper wound care and follow-up appointments with a healthcare provider.

Fistula

• Fistula is an abnormal connection between two areas of tissue or organs.

• It can form due to abnormal wound healing.

• Complications can arise from fistulas.

• Tracheoesophageal fistula is an example.

• It connects the trachea and esophagus.

• Aspiration of esophageal contents can obstruct the trachea.

Key Information for Adhesions

• Adhesions are abnormal bands of internal scar tissue.

• They can form after invasive surgical procedures.

• Adhesions can limit mobility if they form within a joint.

• Adhesive capsulitis of the shoulder (frozen shoulder) is an example.

• Adhesions can form around internal organs, causing pain or obstruction.

• Surgical excision may be required to remove adhesions.