Flashcards in Chronic Inflammation I: Tissue Regeneration and Wound Healing Deck (37):
What are the major cellular players in chronic inflammation?
- plasma cells
- fibroblasts that replace the damaged, inflamed tissue with scar tissue
What is chronic inflammation?
Inflammation of prolonged duration in which active inflammation, tissue destruction, and repair are occurring simultaneously.
What are the three major causes of inflammation?
- persistent infections
- autoimmune response
- prolonged exposure to toxic agents
What are some examples of persistent infections?
viruses, fungi, parasites, and mycobacteria (a special class of microorganisms, of which one species causes TB)
What are some examples of autoimmune response?
- a pathologic immune reaction that develops against a patient's own tissue
ex: rheumatoid arthritis, systemic lupus erytehmatosus
What are some examples of prolonged exposure to toxic agents?
- exposure to asbestos or coal causing pulmonary inflammation and fibrosis
- alcohol abuse causing liver cirrhosis
What are the three morphologic features of chronic inflammation?
- infiltraton with MONONUCLEAR CELLS (macrophages, lymphocytes, and plasma cells)
--> in cases of sufficient duration, organized lymphoid tissue with germinal centers may form
- TISSUE DESTRUCTION, due to the persistence of the injury process
- healing by CT replacement (scar formation or FIBROSIS), with proliferation of blood vessels (ANGIOGENESIS)
What are the main functions of macrophages in chronic inflammation?
(in tissues, monocytes differentiate into macrophages)
- recruited early in acute inflammation
- activated by cytokines, bacterial toxins, or other stimuli
- secrete substances that propagate inflammatory response for killing microbes and initiating repair
- prolonged interaction with host tissue can cause tissue injury and fibrosis
- immobilized at site of injury so as not to go harm other areas
- toxic products released from macrophages (reactive oxygen species and enzymes that degrade proteins or ECM)
Unregulated inflammation can cause tissue damage. What two types of substances do macrophages secrete that can injure host tissues?
- reactive oxygen species (free radicals that are highly reactive and will react with the first thing they encounter, possibly causing host damage)
- proteases: enzymes that degrade proteins or ECM
What recruits B and T lymphocytes to location of chronic inflammation?
Plasma cells are derived from what cells? What do plasma cells produce?
- derived from B-lymphocytes
- produce antibodies against persistent antigens
Eosinophils are important for reactions involving what immunoglobulin? For what type of reaction?
- IgE (usually allergic reactions)
- also important for parasitic infections
Mast cells display a surface receptor for what immunoglobulin?
- binding of IgE results in the release of histamine in acute inflammation
- in chronic inflammation, mast cells produce cytokines that either promote or limit inflammation, dependong on the particular situation
In chronic inflammation, what do mast cells produce?
in chronic inflammation, mast cells produce cytokines that either promote or limit inflammation, dependong on the particular situation
Neutrophils are present for acute inflammation or persistent injury/stimulus; or because they are recruited by what cells?
activated macrophages and T lymphocytes
What are the differences between embryonic and adult stem cells?
Embryonic stem cells:
- pluripotent (multiple potential)
- found in developing embryo
- can differentiate into all the cells of the body
Adult stem cells:
- more limited capacity for differentiation
- found in specific sites in multiple organs
- called tissue stem cells outside of bone marrow
- critical for reconstituting an organ after injury
Epidermal growth factor (EGF)
- stimulates growth of a variety of epithelial tissues, hepatocytes, and fibroblasts
- produced by keratinocytes in the skin, macrophages, and other inflammatory cells
Hepatocyte growth factor (HGF)
- stimulates growth in various epithelial cells, including hepatocytes and bile duct cells
- promotes cell migration in development
- produced mainly by fibroblasts and endothelial cells
- many tumors express receptors for HGF
Vascular endothelial growth factor
- induces formation of blood vessels, both in development (vasculogenesis) and in adults (angiogenesis), the setting of chronic inflammation, wound healing, and tumor growth
Platelet derived growth factor (PDGF)
- stimulate the proliferation and migration of fibroblasts, smooth muscle cells, and monocytes
- produced by a variety of cells, including platelets, activated macrophages, and endothelial cells
Fibroblast growth factor (FGF)
- produced by a variety of cells
- important for the migration of macrophages, endothelial cells, and fibroblasts into damaged tissues for wound repair
- also important in stimulating growth of keratinocytes in skin, and promoting angiogenesis, hematopoesis, and devellopment
Transforming growth factor beta (TGF-beta)
- potent stimulator of fibrosis
- stimulates the proliferation of fibroblasts and smooth muscles, activates fibroblasts and enhances the production of collagen and other components of the ECM
- produced by a variety of cells, including macrophages, endothelial cells and platelets
What are the six important growth factors in tissue regeneration and repair?
- vascular endothelial
- platelet derived
- transforming growth factor beta
What are the main components of granulation tissue?
- consists of new small blood vessels and proliferating, activated fibroblasts
- the vessels are leaky, leading to an edematous or reddened appearance
- characteristic red, granular appearance
- the bridge between injury and formation of scar tissue
What are two separate mechanisms of angiogenesis?
- growth from endothelial precursor cells: specialized stem cells are stored in the bone marrow and recruited to the site of injury to initiate angiogenesis
- growth from pre-existing vessels: vessels dilate, endothelial cells migrate towards stimulus and proliferation, and the tissue is remodeled into small tubules
What are the three main processes of scar formation?
- fibroblast migration and proliferation
- deposition of the ECM
- tissue remodeling
What is involved in fibroblast migration and proliferation (a process of scar formation)?
growth factors like TGF-beta and PDGF stimulate fibroblasts to migrate and proliferate to the site of injury; macrophages secrete many of these factors
What does deposition of the ECM (process of scar formation) involve?
The growth factors also stimulate the synthesis of collagen (in addition to fibroblasts). Fibroblasts will lay down type III collagen first. As repair progresses, angiogenesis stops, and the number of endothelial cells and fibroblasts decreases. The scar will be relatively pale.
What does tissue remodeling (a process of scar formation) involve?
Collagen type III will transition to collagen type I, a denser type of collagen. The body will synthesize and degrade the ECM to form an appropriate balance for the location of the scar. Matrix metalloproteinases perform this function.
Cutaneous wound healing generally progresses through what three steps?
- inflammation (formation of blood clot which helps trigger inflammation)
- proliferation (granulation tissue formation and re-epithelialization of skin surface)
- maturation (ECM deposition, scar maturation with wound contraction and recovery of tensile strength)
What are the two types of wound healing?
- "first intention"/"primary union" (tissue edges closely approximated)
- "second intention" (filling in of a large defect with separated edges, usually due to significant tissue loss)
Describe the process of wound healing (first intention, but generally the same for second intention")
- blood and fibrin move in, form clot
- neutrophils appear (24 hrs), epithelial cells move in and deposit basement membrane material until thin continuous epithelial layer formed
- days 3-5: granulation tissue formed, angiogenesis begins, epidermal layer thickens
- week 2: maximal accumulation of collagen and proliferation of fibroblasts
- first month: scar is mature, inflammation largely gone, tensile strength of scar will continue to increase over several months
What are four differences between the processes of second and first intention wound healing?
In second intention:
- inflammatory response is more intense
- more granulation tissue is formed
- the wound contracts due to actions of myofibroblasts (specialized fibroblasts with some characteristics of smooth muscle) to decrease the gap between dermal edges
- the resulting scar is more prominent and the overlying epidermis is thinned
What are the four systemic factors that impact wound healing?
- nutritional status (i.e. protein deficiency)
- circulatory status
- diseases such as diabetes
- use of anti-inflammatory medications such as glucocorticoids (reduce inflammation, but inhibit collagen synthesis)
What are the three local factors that impact wound healing?
- mechanical factors such as motion, foreign bodies
- size, location, and type of wound
What are the three complications in wound healing?
- deficient scar formation (wound separation, ulceration)
- excessive tissue formation (i.e. excessive granulation tissue, formation of a hypertrophic scar or keloid, or a pathologic fibroblastic response called "fibromatosis")
- formation of contractures (exaggerated contraction of wound leads to distortion of scar or adjacent structures, seen in severe burns)