3 - Inflammation and Repair Flashcards
What is the purpose of inflammation?
To bring cells and molecules of host defense from the circulation to a site of tissue damage to remove the offending agents.
What are the two main participants in inflammation?
Blood vessels and leukocytes
Do leukocytes have short or long life spans in tissues?
Short
What are the cardinal signs and symptoms of inflammation?
Rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function)
What family of receptors senses the presence of foreign microbes?
Toll-like receptors (also, circulating antibodies and complement)
Intracellular sensors can sense what molecules that indicate possible damage to the cell?
ATP (indicating mitochondrial leakage), low potassium (indicating cellular leakage), uric acid (indicating DNA breakdown), DNA (indicating nuclear leakage)
Damage sensors in the cell trigger the formation of what structure?
The inflammasome
What does the inflammasome produce?
Interleukin-1
What are the general steps of inflammation?
(1) Recognition of the injurious agent, (2) recruitment of leukocytes, (3) removal of the agent, (4) regulation of the response, (5) resolution and repair
What are the three major components of acute inflammation?
Dilation of small blood vessels, increased permeability of the microvasculature, migration of the leukocytes to the damaged tissues
Why do blood vessels dilate in inflammatory situations?
To increase blood flow to the area and slow down the blood flow
What is the principle inflammatory mediator leading to vasodilation?
Histamine (and also kinins)
What do endothelial cells increase expression of during the inflammatory response?
Adhesion molecules (for leukocyte attachment)
What is the most common method increased vascular permeability? What are other methods?
Endothelial cell shrinkage (increasing the interendothelial space); direct endothelial damage and necrosis, vascular endothelial growth factor
What vessels proliferate during inflammatory responses?
Blood and lymph vessels
Define lymphangitis. Define lymphadenitis.
Lymph vessel inflammation; lymph node inflammation
What is the cause of the red streaks seen coming from an infected wound?
Lymphangitis
What are the three steps of leukocyte migration in the blood vessel lumen?
Margination, rolling, and adhesion (all to activated endothelium)
What adhesion molecules assist leukocytes in the rolling phase?
Selectins
What adhesion molecules assist leukocytes in the adhesion phase?
Integrins
What is the name of the process by which leukocytes leave the blood vessel? What molecules assist in this process?
Diapedesis (also known as transmigration); PECAM-1 and CD31
When does chemotaxis occur?
After diapedesis when a leukocyte has entered the tissue space
What are the three principal chemokines involved in chemotaxis?
Interleukin-8, C5a, and leukotriene B4
What is the first responder in acute inflammation? What leukocyte will replace the first responder within 24-48 hours?
Neutrophils (more abundant, quicker, short half-life); macrophages (less abundant, slower, longer half-life, can proliferate in tissues)
What three drugs are especially effective in interfering with tumor necrosis factor and inhibiting harmful inflammation?
Etanercept, infliximab, adalimumab
What happens to the leukocytes post-chemotaxis once they reach the site of injury?
(1) They recognize the offending agents (toll-like receptors); (2) they become activated and phagocytic
What are the three steps of leukocyte phagocytosis?
Recognition, engulfment, and killing (or degradation)
What leukocyte receptors identify bacteria but not host cells?
Mannose receptors
What combines with the phagosome containing a phagocytosed bacteria or other agent within the leukocyte?
A lysosomal granule (containing reactive oxygen species and degradation enzymes)
How are foreign microbes killed within the body?
Mainly reactive oxygen species (the respiratory burst within the phagolysosome)
What type of nitric oxide synthase is implicated in ROS formation?
Inducible NOS (iNOS)
What enzymes do neutrophil lysosomes contain?
Lysozyme, hydrolytic enzymes, myeloperoxidase, and lactoferrin
What are neutrophil extracellular traps?
Fibrillar networks released by neutrophils to trap microbes and kill them with antimicrobial substances
What substances are released to limit and end inflammation?
Lipoxins, transforming growth factor-beta, interleukin-10
What are some of the principal mediators of inflammation?
Vasoactive amines (e.g. histamine and serotonin), prostaglandins, leukotrienes, cytokines, and complement
What are the sentinel cells of inflammation?
Mast cells, dendritic cells, macrophages
What are the products of cyclooxygenase degradation of arachidonic acid?
Arachidonic acid –> Prostaglandin G2 –> Prostaglandin H 2–> Prostacyclin (prostaglandin I2) + Thromboxane A2 + Prostaglandins D2 and E2
What are the products of 5-lipooxygenase degradation of arachidonic acid?
Hydroperoxide (5-HPETE) –> Leukotriene A4 –> Leukotriene B4 + C4 + D4 + E4 AND Hydroperoxide (5-HPETE) –> Lipoxin A4 + B4 (antiinflammatory)
Why do COX-2 inhibitors increase the risk of adverse cardiovascular events?
They inhibit prostacyclin formation but leave thromboxane A2 formation untouched
What benefits do COX-2 inhibitors show?
Decreased renal and gastrointestinal damage
Of which molecules do corticosteroids decrease gene expression?
COX-2, phospholipase A2, iNOS, interleukin-1, TNF
What are the principal types of exudate?
Serous, purulent, fibrinous
Define ulcer.
An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue
What are the potential outcomes of acute inflammation?
Resolution, fibrosis, and progression to chronic inflammation
How long does chronic inflammation last?
Weeks to months
What processes coexist in chronic inflammation?
Inflammation, tissue damage, and tissue repair
What are some causes of chronic inflammation?
Persistent infections, hypersensitivity disorders, prolonged exposure to toxic agents
What morphological changes characterize chronic inflammation?
Mononuclear cell infiltrate (macrophages and lymphocytes), tissue destruction, attempts at tissue healing (angiogenesis and fibrosis)
Which cell is the major actor in chronic inflammation?
The macrophage
What does classical activation cause macrophages to do? What does the alternative activation cause macrophages to do?
Microbicide; tissue repair
What is granulomatous inflammation? What is its purpose as a form of chronic inflammation?
Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis; a cellular attempt to contain an offending agent that is difficult to eradicate.
What are the two types of macrophages seen in granulomas?
The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells.
What are the two main types of granuloma?
Foreign body granulomas and immune granulomas
What is a foreign body granuloma?
Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage and do not incite any specific inflammatory or immune response.
What is an immune granuloma?
Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T cell-mediated immune response.
What is the name of the collective signs and symptoms of the systemic effects of inflammation?
The acute-phase response
Which cytokines are the principal mediators of the acute-phase response (systemic effects of inflammation)?
TNF, IL-1, IL-6, interferons
What are the principal effects of the acute-phase response (systemic effects of inflammation)?
Fever, C-reactive protein, leukocytosis, and (in severe cases), septic shock
What family of factors causes proliferation of hematopoietic stem cells in the bone marrow?
Colony-stimulating factors
Which parenchymal organ has remarkable regenerative capacity? It can grow back after loss of what percentage of its cells?
The liver; 90%
Which parenchymal organs have partial regenerative capacity?
The lungs, adrenal glands, thyroid, and pancreas
How does the liver regenerate?
The proliferation of remaining hepatocytes and the regeneration from progenitor cells
What are the steps of scar formation?
Angiogenesis, granulation tissue formation, remodeling of the scar tissue
What role do macrophages play in tissue repair?
They phagocytize debris from the wound and secrete growth factors and cytokines to promote tissue growth
Describe the process of angiogenesis.
How is new connective tissue deposited in scar formation?
Fibroblasts migrate to the area and release ECM (transforming growth factor-beta is the most important cytokine in this process)
Define healing by first intention (or primary union).
Healing when the injury involves only the epithelial layer
One of the simplest examples of this type of wound repair is
the healing of a clean, uninfected surgical incision approximated by surgical sutures.
Define healing by second intention (or secondary union).
When cell or tissue loss is more extensive, such as in large
wounds, abscesses, ulceration, and ischemic necrosis
(infarction) in parenchymal organs, the repair process
involves a combination of regeneration and scarring.
Carefully sutured wounds have what percentage of the strength of normal skin?
~70%
After suture removal (1 week later), what percentage of the strength of unwounded skin does the healing skin have?
10%
What percentage of unwounded skin strength does the healing skin have after 3 months?
70-80% (there will likely be no substantial improvement beyond that)
What is the condition of an organ upon excessive deposition of collagen and scar tissue?
Fibrosis
If a scar is raised due to excess collagen deposition, what is it called?
A hypertrophic scar
If a scar grows outside the boundaries of a wound and does not regress, what is it called?
A keloid (more common in African-American patients)
What is it called when excessive granulation tissue is deposited and it rises above the skin (disrupting reepithelialization)?
Exuberant granulation (must be removed by cautery or surgery to allow skin healing)
Although contraction is an important part of the healing process, what is an excessive amount if contraction called? (often seen in burn patients)
A contracture
What are two types of complication in wound healing when insufficient granulation or scar tissue is laid down?
Dehiscence (wound rupture) or ulceration
