Mechanisms of Disease #29
Tuesday April 29, 11am
Dr. Putthoff
Jennifer Thompson
Page 1 of 6
Intro to Chapter 4: Tissue Repair, Cellular Growth, Fibrosis and Wound Healing
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Dr. Putthoff commented that the lectures will sometimes have to be after the test
(like this one).
He noted that we should check our e-mails regularly for pertinent course
information, and he stressed again that we DO NEED THE BOOK.
He then reviewed things we had gone over thus far – noted overlap of concepts
2 major things happen after injury:
o removal of debris due to dead cellular debris left over
o repair – usually by fibrotic scars (except in brain and a few other places)
In a properly-functioning immune system, healing begins almost as soon as
inflammation – that is, there is significant overlap of the two processes
Chapter 4 is based on tissue repair – Dr. Putthoff warned us that the material is
extremely dense in terms of soluble and non-soluble factors related to repair
“Please note that for exam 2, in addition to the two assigned chapters in Robbins,
you are responsible for chapter 9, “Serum Proteins,” in the Handbook of Clinical
Pathology, and for the cases under “Inflammation and Repair” (excepting case 2,
note that there was a misprint in Dr. Putthoff’s original powerpoints on this),
on the Interactive CD-ROM (available on the web) – read them and peruse the
L.O.’s.”
o Also use Dr. Putthoff’s powerpoint slides as a study guide (look at “study
tips” from previous presentation)
o Remember, any element from the text that appears as a major topic,
bolded or in italics should be emphasized. (See Dr. Putthoff’s assistant,
Nancy Lee, in room 318 if you are having problems obtaining the book.)
Control of the cell cycle
o Know what is normal in terms of the cell cycle (Fig 4-2), pg. 90
 Some cells are quiescent – incapable of dividing and remain in G0
phase of cell cycle
o And how things may go awry in terms of the cell cycle
 Figs 4-7, A & B, pg. 96 – what goes w/ cell cycle
 Fig 4-4, pg. 93 – overview of signal transduction systems
(important)
o Note all major topics. Be able to delineate, define and know whtat the
soluble and non-soluble
o Major topics – Concepts – Italicized
o DON’T memorize Fig 4-3, 4-5, 4-6, or Table 4-1 on pg 97
Mechanisms of Disease #29
Tuesday April 29, 11am
Dr. Putthoff
Jennifer Thompson
Page 2 of 6
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The inset in the picture at right shows the
basilar portion of the skin, containing
basilar cells (stem cells of skin),
melanocytes, and a dendritic cell
The next slide shows the epidermis at edge
of a skin ulceration, in the region where
active repair is taking place.
o Keratinocytes elaborite certain
cytokines and growth factors in collaboration with dermal cells
Repair by connective tissue (fibrosis and scarring)
o Necrotizing inflammation @ chronic inflammation
 Angiogenesis
 Migration/proliferation of fibroblasts
 Deposition, ECM
 Remodeling
o Know 1st 4 major collagen types, pg 99
 Type IV is the most ubiquitous
o Granulation tissue – new tissue laid down by connective tissue repair
 Grossly (usually in approx. 3-5 da.), appears pink and soft
 Histopathology: many small delicate blood vessels and
proliferating fibroblasts; often, very edematous
 Torn easily if disrupted (especially if tension); very delicate
 Dehiscence – disruption of tissue; tearing of granulation
tissue; causes a very broad scar
o Picture at right is two stains of granulation tissue:
 notice few cells,
lots of BV’s
 fibroblasts
compose majority
of cells present
Angiogenesis – via angioblasts
o BV’s are frequently destroyed in injury
o Vasculogenesis
 Angioblasts
o Neovascularization
o Increased permeability
through gaps and
transcytotis is favorable
since granulation tissue
depends on a lot of
growth factors
Mechanisms of Disease #29
Tuesday April 29, 11am
Dr. Putthoff
Jennifer Thompson
Page 3 of 6
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o New sprouts are still trying to inflammatory cells to remove necrotized
tissue that is in the way
Growth factors and receptors
o VEGF: the most important growth factor in both physiologic and
pathologic angiogenesis (neoplasia); in adult tissue
 Expressed at low levels in quite a variety of tissues but at higher
levels in certain tissues, e.g., glomerular podocytes and myocardial
cells
o Maturation and remodeling occurs – especially in hard tissues such as
cartilage and bone
o Angiopoietins
o See Table 4-3, pg. 105 – don’t memorize, just know in general inducing
agents, and functions of VEGF
o ECM proteins as regulators of angiogenesis
Fibrosis – (scarring)
o Of the growth factors involved in inflammatory fibrosis TGF-
(transforming growth factor beta) appears to be the most important
o TGF- is produced by most of the cells in granulation tissue and appears
to be highly related to
 Fibroblast migration and proliferation
 Increased synthesis of collagen and fibronectin
 Decreased degradation of the ECM
Extracellular Matrix
o Collagen accumulation/collagen destruction
o Tissue remodeling – may be laid down inappropriately – body will remove
and do again
 Transition from granulation tissue to a scar (dense hyaline fibrosis,
in most cases), involves transition in the composition of the ECM
@ matrix metalloproteinases (MM) – KNOW THESE!: What
stimulates, inhibits, or activates them (KNOW THIS)?
 Role of zinc ions? – seems to play a role in healing
 MM should be distinguished from MBMM
 MM are rapidly inhibited by TIMP
Wound Healing
o A complex but orderly process
 Induction, acute inflammation
 Regeneration (parenchymal cells)
 Migration and proliferation
 Synthesis, ECM
 Remodeling
Mechanisms of Disease #29
Tuesday April 29, 11am
Dr. Putthoff
Jennifer Thompson
Page 4 of 6
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 Collagenization; increasing wound strength
Healing by first intention – important to know; may be mentioned on surgery
rotation
o Death of a certain number of epithelial cells and CT cells
o Disruptions of epithelial BM (basal membrane) continuity
o Narrow space immediately fills with clotted bloods and fibrin; dehydration
forms the scab
o Within 24 hrs.
 Polys
o Within 24-48 hrs.
 Cut edges
thicken
due to
prolif. of
basal cells
and spurs
of EP
(epithelial) cells from the edges migrate and grow along the cut
margins of the dermis
o Melanocytes can be seen at the right edge of the above picture
o Elevation of dermis are dermal papilla, and downward extensions of
epithelium is referred to as rete pegs
o Picture shows basalar proliferation of cells in normal skin
o Dermal-epidermal interface is site of action
o Dermis – location of lymphatics and BV’s; remember if collagen fibers
are damaged by agents such as sun exposure they look like cooked bacon
Healing by second intention
o More extensive loss of cells and tissues; large defects
o Abundant granulation tissue
o Differs from first intention
 More intense inflammation
 Contraction @ myofibroblasts
o Primary or secondary intention healing depends upon the nature of the
wound
Compare the patterns of
wound healing in
healing by first and
second intention
Healing by first
intention leaves a
Mechanisms of Disease #29
Tuesday April 29, 11am
Dr. Putthoff
Jennifer Thompson
Page 5 of 6
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narrow scar, whether sutured or not (often sutured)
Healing by second intention is cosmetically ugly, and leaves a huge broad scar;
usually occurs in people who haven’t sought medical attention or in someone with
an infected wound or in cases of wound dehiscence (splitting open)
Remember that a laceration is due to a blunt force by definition; injury due to
things like knife/razor wounds are correctly referred to as
Wound strength – answers to below questions are right in the book (HINT, HINT)
o How long does it take for a wound to achieve its maximal strength?
o From which molecular elements (and from what features of those) is
(wound) strength derived?
Next graph shows the overlap of inflammation, repair, and eventual wound
contraction
Summary – the healing wound: the prototype of tissue repair
o early phase – inflammation
o fibroplasias
o tissue remodeling
o scarring
 The amazingly precise and thoroughly impressive orchestration of
healing/repair under normal conditions almost certainly lies in the
regulation of specific soluble mediators and their receptors on
particular cells; cell-matrix interactions; and a controlling effect
of physical factors, including forces generated by changes in cell
shape
Local and systemic factors that influence wound healing
o **tissue repair may be greatly influenced by a significant number of
known and some unknown influences
o Systemic
 Nutrition
 Metabolic status/disease
 Circulatory status
 Hormonal influences
o Local host factors
 Infection (single most important factor in delayed or non-healing
 Mechanical factors
 Foreign bodies
 Size, location and type of wound
**Pathologic aspects of wound repair
o deficient scar formation
 inadequate formation of granulatin tissue
 wound dehiscence
 ulceration (e.g., poor vascularity or neuropathy)
Mechanisms of Disease #29
Tuesday April 29, 11am
Dr. Putthoff
Jennifer Thompson
Page 6 of 6
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o excessive formation of the repair components
 keloid – more common in African-Americans; hypertrophic scars;
exuberant wound healing (see
picture at right) – goes far beyond
boundaries necessary to adequately
heal a wound
 hypertrophic scar
 exuberant granulation tissue
formation
 aggressive fibromatosis
o formation of contractures
The mechanisms underlying wound repair are similar to those occurring in certain
systemic diseases characterized by chronic inflammatory fibrosis, such as
rheumatoid arthritis, pulmonary fibrosis and cirrhosis of the liver
o How do the latter differ from the orderly progression of wound
inflammation?
Review this diagram on acute inflammatory exudation:
Not shown above are the pathways to chronic inflammation. This persistent in
jury commonly results in tissue destruction and scarring, although neoplasia could
be the result, as well.
Overview of the inflammatory-reparative response
o “the processes of inflammation and repair underscore the remarkable
capacity of the body to restore itself, far surpassing any device made by
humans”