Chronic Inflammation, Wound Healing and Angiogenesis, Nomenclature of Inflammation

Lecture 14

When does chronic inflammation occur?

• acute inflammatory response fails to eliminate inciting stimulus

• after repeated episodes of acute inflammation in whcih there is extensive tissue injury and necrosis

• response to unique biochemical characteristics and/or virulence factors in the inciting stimulus or microbe

Why does chronic inflammation occur?

• acute inflammatory response failed so chronic response then isolates by dense accumulations of cells and fibrolblasts or walls off substance with collagen

What are the features of chronic inflammation?

• shift in inflammatory cells from neutrophils to lymphocytes, natural killer cells, macrophages, plasma cells, and multinucleate giant cells

• proliferation of fibroblasts and deposition of collagen and neovascularization

What are examples of persistent infections?

• Bacteria: Mycobacterium spp, Nocardia spp

• Fungal agents: Blastomyces dermatidis and Histoplasma capsulatum

• Parasites: Toxocara canis larvae

What are common sequelae to persistent infections?

• tissue destruction

• granulomatous inflammation

• fibrosis

What microbes are able to isolate themselves from immune response and antimicrobial drugs by “hiding” in pus?

Steptococcus and Staphylococous spp

What foreign materials are virtually indestructible and unresponsive to pahgocytois or enzyme breakdown?

• plant material

• grass awns

• silica dust

• asbestos fibers

• some suture materials

• surgical protheses

Alterations in the regulation of adaptive immune responses to self antigens result in what?

autoimmune diseases like lupus

What is one example of where the cause of chronic inflammation remains unknown?

canine granulomatous menigoencephalitis

What is the mechanism of abscess formation?

• inciting inflammatory stimulus not eliminated

• inflammatory mediators from neutrophils (myeloperoxidase enzyme) in the erudite liquefy the affected tissue

• pus is formed

What are the cellular components of an abscess?

neutrophils admixed with cell debris, macrophages, and fribroblasts with variable infiltrates of lymphocytes

Fibroblasts produce collagen and ECM proteins to form a what?

a thin vascularized connective tissue rim that antibiotics can penetrate

The thin connective tissue rim formed by fibroblasts can mature into what?

a thick fibrous capsule to wall off the exudate from normal tissue but this is difficult for antibiotics to penetrate

What is a sterile abscess?

incompletely degraded foreign material

What is a septic abscess?

one formed by pyogenic bacteria like Staph or Strep

The color of the abscess exudate often depends on what?

the pigment produced by the inciting bacterium

What color abscess exudate is formed by Staphyloccus, Streptococcus spp, and Corynebacterium ovis?

yellow

What color abscess exudate is formed by Pseudomonas aeruginosa?

green

What color abscess exudate is formed by Serratia marcescens?

red

What are the major cell types involved in granulomatous inflammation/granuloma?

• macrophages

• epitheloid macrophages

• multinucleated giant cells

What is the cellular pattern of a granuloma?

mass or nodule of cells

What is the cellular pattern of granulomatous inflammation?

diffuse sheets

Granulomas are mediated by what immune response?

TH1

Granulomatous inflammation is mediated by what immune response?

TH2

What microbes form granulomas?

• Mycobacterium bovis

• Mycobacterium tuberculosis

• Coccidiomycosis

What microbes form granulomatous inflammation?

• Mycobacterium paratuberculosis (Johne’s disease)

Nodular (TH1) granulomas are what in appearance?

• gray to white

• round to oval

• firm to hard

What are the cellular components of nodular (TH1) granulomas?

macrophages +/- epitheloid macrophages/multinucleated giant cells bordered by fibroblasts, lymphocytes and plasma cells

Caseating nodular granulomas have what?

central thick pasty necrotic material

Noncaseating nodular granulomas lack what?

central necrosis

Tuberculosis causes what type of nodulating granulomas?

caseating

Describe stage I of granuloma formation.

• days after infection

• lesion site is infiltrated by neutrophils, monocytes, macrophages, gamma/delta T lymphocytes, NK cells, epitheloid macrophages

Describe stage II of granuloma formation.

• 48 hours to multiple days and weeks

• macrophages, epithloid macrophages, thin rims of fibrous connective tissue, variable numbers of NK cells, and gamma/delta T lymphocytes, as well as alpha/beta T lymphocytes and B lymphocytes

• multinucleated giant cells

Describe stage III of granuloma formation.

• weeks to 1 month

• central area can caseate (necrosis) or become dense with macrophages and mineralize

• lymphocytes, plasma cells, fibroblast, and a fibrous connective tissue capsule surrounds core

Describe stage IV of granuloma formation.

• several weeks to months

• walled off by a dense capsule, and regions within the lesion can become mineralized and overtake the surrounding tissue

Diffuse granulomatous inflammation (TH2) has what appearance?

• gray to white

• expansile but poorly demarcated from adjacent tissue

• firm

What are the cellular components of eosinophilic granulomas?

• numerous eosinophils with macrophages

• varying lymphocytes and plasma cells

What type of eosinophilic granulomas are seen in felines?

eosinophilic plague, granuloma, dermatitis

What type of eosinophilic granulomas are seen in canines?

eosinophilic granuloma of the oral cavity of huskies and other dogs

What type of eosinophilic granulomas are seen in equine?

equine collagenolytic granuloma, axillary nodular necrosis, and unilateral papular dermatitis

What type of eosinophilic granulomas are seen in all species?

eosinophilic (TH2) granulomas secondary to parasitic infection

What are the effector cells of chronic inflammation?

• monocytes/macrophages

• epithleoid macrophages

• multinucleated giant cells

• dendritic cells

• T and B lymphocytes

• Plasma cells

• eosinophils

• mast cells

• natural killer cells

• fibroblasts

• endothelial cells

• platelets

What is the signature cell of chronic inflammation?

monocytes/macrophages

Macrophages are activated by what?

microbial products or by cytokines from immune activated T lymphocytes

Macrophages activated by T lymphocytes releasing IFN gamma further mediate what?

inflammation and tissue injury

Macropahges activated by T lymphocytes releasing IL-4 mediate what?

fibrosis and repair

What are the products made by activated macrophages that cause tissue injury and fibrosis?

• arachidonic acid

• platelet derived growth factor

• fiborblast growth factor

• transforming growth factor beta

What are the sources of macrophages?

• bone marrow

• tissues

• spleen

What is the role of monocytes/macropahges in chronic inflammation?

• detect intial activity of acute inflammation

• migrate in response to chemotaxins

• remove and kill microbial agents by pahgocytsosi

• remove and degrade particulate matter by phagocytosis

• process antigens for presentation to effector cells of teh adaptive immune reponse

• facilitate angiogenesis and remodel the ECM

What cells are larger than activated macrophages, are abundant in the cytoplasm with polygonal shape, and can resemble epithelial cells?

epitheloid macrophages

What cells form when two or more macrophages create one large cell and are a foreign body type with nuclei haphazard at center of the cell?

multinucleated giant cells

What type of giant cell has the nuclei in a horseshoe arrangement?

langerhans type

Lymphocytes has a key role in which chronic inflammatory processes?

• autoimmune diseases

• diseases with persistent antigen

What is the cellular pattern of lymphocytes?

• surround blood vessels (perivascular aggregation)

• surround granulomas

• haphazardly infiltrate the tissue

What cells are important in coordinating adaptive immune response?

T lymphocytes

Which lymphocytes are differentiated into plasma cells?

B lymphocytes

Dendritic cells originate from what?

monocytes

Dendritic cells are nearly present in all tissues, but are most numerous where?

• skin

• mucosal surface of respiratory and GI tract

What cells have filipodia (finger like protrusions extending from cell surface)?

dendritic cells

What is the main function of dendritic cells?

• antigen processing and presentation to T cells

• stimulation of adaptive immunity (sentinel cells)

Plasma cells secrete immunoglobulins that do what?

bind to and opsonize antigens to facilitate phagocytosis

Plasma cells predominate in what chronic conditions?

• feline and canine inflammatory bowel disease

• feline pododermatitis

• feline lymphoplasmacytic stomatitis

• chronic dermatits across species

• interstitial nephritis in dogs and cats

What are opsonins?

molecules that bind to pathogens, making them more attractive to phagocytes

Give examples of opsonins

• antibodies (immunoglobulins)

• complement proteins (i.e. C3b)

What are the steps of opsonization?

• coating

• phagocyte recognition

• engulfment

• degradation

Describe the coating stage of opsonization.

• first step

• opsonins bind to the surface of a pathogen, creating a “handle” that phagocytes can recognize

Describe the phagocyte recognition stage of opsonization.

• second step

• pahgocytes have receptors on their surface that can bind to opsonins, specifically the Fc region of antibodies or complement receptors

Describe the engulfment stage of opsonization.

• third step

• once the opsonized pathogen is bound to the pahgocyte, the phagocyte engulfs it, forming a structure called a phagosome

Describe the degradation stage of opsonization.

• fourth and final step

• the phagosome fuses with lysosomes (organelles containing enzymes), forming a phagolysozome

• the pathogen is then broken down and digested by the enzymes

What are the elongated spindle shaped cells that synthesize collagen and extracellular matrix proteins and are involved in the formation of fibrosis in chronic inflammation?

fibroblasts

What are the three potential healing responses/outcomes?

• a return to normal structure and function

• healing by replacement fibrosis

• healing by sequestration

The degree of healing is impacted by?

• severity of inflammation

• ability of remaining cells to regenerate

• inciting cause

Describe a return to normal structure and function.

• minimal damage to tissue framework/basement membranes

• return to function via regeneration, cell migration and reepithelialization

Describe healing by replacement fibrosis.

• more severe damage (necrosis) and loss of tissue frameowrk and needed cells for repair

• fill in necrotic region with immature fibrous connective tissue

• form scar or graulation tissue

Describe healing by sequestration.

• unable to fully remove inciting issue

• abscess or granuloma formation

What are the four phases to repair a wound?

• hemostasis

• inflammation

• proliferation

• remodeling

Which phase of wound repair is described:

• immediately after injury - transected blood vessels

• platelets adhere to exposed collagen and act to plug exposed vessels

• intiate angiogenesis

hemostasis

Which phase of wound repair is described:

• full swing 24 hours after intiial injury

• cardinal signs (redness, swelling, heat, pain, loss of function)

inflammation

Which phase of wound repair is described:

• 3-4 weeks or longer

• migration of cells to bridge the wound

• generation of endothelial cells (angiogenesis), epithelial cells (epithelialization), connective tissue stroma (fibroplasia)

proliferation

Which phase of wound repair is described:

• after completion of inflammation and proliferation

• maturation/contraction

• granulation tissue

• can last up to two years

remodeling

What cells align to planes of tissue lines (tension lines)?

fibroblasts

Which cytokine has a major role in fibroblast activity and collagen deposition?

TGF-beta

Which species ha fibroblasts that are extremely responsive to tissue injury which is why we worry about vaccine induced fibrosarcomas and traumatic lens rupture?

cats

What type of healing has the edges of a non-septic wound in close proximity and is the goal of your surgical repair?

first intention

What is the outcome of first intention healing?

• little trace of thw wound over time (mild fibrosis/loss of hair)

• tensile strength nearly the same

The following mechanism matches which type of healing:

• hemorrhage/cells —> phagocytized and removed by macrophages

• new blood vessel proliferate into lesions (angiogenesis)

• ECM synthesized to fill in gap left from inflammation

• collagen will continue to fill in defect

• re-epithelialization over the top of the wound

first intention

Which type of healing does not have cut edges in close apposition so the collagen/fibroplasia fills in defect in a more haphazard way and results in delayed re-epithelialization and can remain ulcerated and result in a hyperplastic scar?

second intention

What variables have an effect on wound healing?

• wound specific variables

• systemic variables

• medications/environment

• disease state

What are wound specific variables?

• location

• infection

• vascular supply

What are systemic variables?

• nutrition

• age

Glucocorticoids reduce what?

inflammatory reponse

Chemotherapy prevents what?

cellular proliferation

Diabetes causes what to be reduced?

• reduced angiogenesis

• less effective leukocytes with elevated glucose

Normal tissue has what oxygenation percent?

90%

What factor promotes angiogenesis and stimulates cell proliferation in hypoxic conditions?

hypoxia inducible factor

What forms within a healing wound?

granulation tissue

What is the specific arrangement of fibroblasts and blood vessels within granulation tissue?

• fibroblasts parallel to wound surface

• capillaries oriented perpendicular to wound surface

If there is excessive granulation tissue in horse wounds, what occurs?

proud flesh (pathologic)

What type of reaction causes formation of extensive connective tissue/fibrosis and/or contraction of connective tissue that places tension on surrounding tissue?

Scirrhous reaction

Contraction of wounds caused by a scirrhous reaction is mediated by what?

myofibroblasts