MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 1 of 8
Tissue Repair, Cellular Growth, Fibrosis, & Wound Healing
I.
Exam Recap
 We did extremely well as a class: 40+ As, 50+ Bs, 6 Fs
 The procedure for this class: They look at the total number of people who failed
the exam. If this is >5%, the mean is adjusted to about 83. If this is <5%, no
adjustment is made. For Exam 1, initially 13 people failed so the mean was
adjusted from an 80.2 to about 84.
 Dr. Puttohoff does NOT throw out any questions as statistically it hurts the top
people in the class because every question counts more if some are thrown out.
 If the adjusted mean puts you over a 100, you’ll get the points back at the end of
the class. This is done to preserve the class rank since residency programs look
at this.
 Post exam review is not for question challenges. Dr. Putthoff goes through all
the questions that statistically could have been a problem.
 This class is the 1st time that we’ve had to begin to evaluate clinical vignettes
and apply them. Word association won’t help much here.
II.
Lecture Intro
 Inflammation and repair overlap.
 In a properly-functioning immune system, healing begins almost as soon as
inflammation begins. This chapter: REPAIR
 Exam 2:
o 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
o for the cases under Inflammation & Repair (except Case 2), 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” previously)
o Remember, any element from the text that appears as a major topic, bolded
or in italics should be emphasized.
 The 1st part of this chapter is dense with mediators. The powerpoints give a
good idea of what Dr. Putthoff wants us to know. He doesn’t think we need
to memorize all of them.
III.
Control of the Cell Cycle
 Know the cell cycle as it is in the book.
 Know what is normal (Fig 4-2), p. 90
o Many cells like neurons, myocytes, and other types of cells are mostly in the
Go, quiescent phase.
 And how things may go awry
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 2 of 8
A.
B.
C.
D.
o Critical: “The body’s ability to replace injured or dead cells and to repair
tissues after inflammation is critical to survival”
o Fig 4-7, A & B, p. 96
o Fig 4-4 p. 93
o Note all major topics, be able to delineate, define & know what the soluble
and non-soluble factors do
o “Major topics – Concepts – “Italicized”
Basilar Cells
 The example given was that epidermal basilar cells are continually in the
presyntheic phase. They’re available at all times to proliferate and go
through maturation.
 The keratinocytes, which are the cells in the epidermis, and the cells in the
dermis interact via chemical mediators: cytokines and others.
Molecular events in cell growth
 “Molecular events in cell growth are complex & involve an increasing
array of intercellular pathways & molecules, but they are important because
it is now clear that aberrations in such pathways may underlie the
uncontrolled growth in cancer as well as abnormal cellular responses in a
variety of diseases.”—especially in proliferative diseases
 “The explosion in understanding of these molecular events has stemmed
largely from the understanding that growth factors induce cell proliferation
by affecting the expression of genes involved in normal growth control
pathways, the so-called protooncogenes.”
 Know the definition of protooncogenes and the differences between
protooncogenes, oncogenes, and tumor suppressor genes even though all
are related to genetic events and some to neoplasia.
Three general schemes of intercellular signaling—Know the definitions of
these 3 and how they work on target cells.
 These are how the cells communicate with each other.
1. Autocrine
2. Paracrine
3. Endocrine
 “Additionally, some membrane-bound proteins present on 1 cell can
interact directly with receptors on an adjacent cell (Fig. 4-3)”
Overall Schematic on p. 93
 This is what he really wants us to know!
 It’s an overview of signal transduction systems and the 4 major
intracytoplasmic pathways. (seen more on USMLE than on COMLEX)
 Molecular events:
o Signaling systems
o Cell surface receptors
o Subsequent intracellular events
o “Feedback Loops”—cause the initial chemical initiator to be inhibited.
Think autocrine loops.
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 3 of 8
IV. Molecular events
A. Transcription Factors
 Know what they are—the major 1 or 2, and be able to define them.
 Know cyclins and cyclin-dependent kinase inhibitors. Know what they
are, be able to define them, and know what they do in the cell cycle.
 Don’t need to memorize things like p21, p27, p57.
B. Checkpoints—Know their influences in the cell cycle
C. Growth inhibition
D. Growth factors
 4 major actions of GF
1. Angiogenesis
2. Wound repair
3. Cellular development and maturation
4. Aspects of hematopoiesis (2)—this 2 means BE ABLE TO ANSWER
THIS
 EGF, TGF, PDGF, VEGF, cytokines—major GF to know
 VEGF is extremely important
V.
Extracellular Membrane (ECM)
 “Cells grow, move & differentiate in the intimate contact with the ECM and
there is overwhelming evidence that the matrix critically influences these cell
functions.”
 ECM is extremely important in neoplasia.
 Define & describe the ECM
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 4 of 8
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Composed of 3 groups of macromolecules—Be able to define these
o Collagen, elastin, fibrillin, and elastic fibers
o Adhesive glycoproteins and integrins
o Matricellular proteins
o Proteoglycans and hyaluronan
Know the 1st 4 types of collagen (p. 99)
Collagen Type IV is very important and comes up frequently in a variety of
diseases, especially in renal disease.
“Cell growth and differentiation involve the cellular integration of multiple
signals. Some of these signals are derived from polypeptide growth factors,
cytokines, and growth inhibitors. Others are derived from components in the
ECM itself and proceed through integrin-dependent signaling pathways.
Although unique pathways may be activated by specific types of receptors,
“cross-talk” between the signaling systems integrates the signals controlling
cell proliferation and other cellular events.”
Fig 4-12 is a model of the interactions between growth factors, ECM, & cell
responses. Note also the secondary mediators, integrins, collagens, actin, and
some myosin. These induce the cell to do all of the functions it needs to
accomplish: proliferation, differentiation, protein synthesis (hepatocytes),
attachment, migration, and shape changes.
o Shape changes allow cells to go through diapedesis.
VI. Repair by connective tissue—fibrosis and scarring
A. Necrotizing inflammation with chronic inflammation
 When you have chronic inflammation, you must go through a remodeling
process. This involves:
o Angiogenesis—occurs typically in granulation tissue
 See vasulogenesis with angioblasts
 Neovacularization is found in most tissues that are capable of
proliferating.
 Angioblasts → Vasculogenesis → Mature vessels → Angiogenesis
→ Maturation and Remodeling until it reprofuses
 Sometimes the tissue becomes necrotic or there’s a lesion that
prevents reprofusion resulting in atrophy.
 Example given was a hemartoma, a benign cartilage nodule filling
the bronchial lumen. Damage is caused distal to it and can cause
adelectasis—collapse of the lung.
o Migration/proliferation of fibroblasts—scarring
o Deposition, ECM
o Remodeling—so that it resembles original structure
B. Granulation tissue
 Usually appears in 3 – 5 days
 Grossly appears pink and soft
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 5 of 8
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C.
D.
E.
F.
Histopathology: many small delicate blood vessels and proliferating
fibroblasts; often, edema
 Has very little tensile strength
Growth Factors and Receptors
 VEGF: the most important GF in both physiologic and pathologic
angiogenesis in adult tissue
 VEGF is expressed at low levels in quite a variety of tissues but at higher
levels in certain tissues like glomerular podocytes (visceral epithelial cells
that line Bowman’s capsule lining the capillary lumen) and myocardial cells.
 Angiopoietins
 See Table 4-3, p. 105
 ECM proteins as regulators of angiogenesis
 Inducing agents? Receptors? Functions**? ** means their functions.
Inflammatory Fibrosis
 Of the GF involved in inflammatory fibrosis, TGF-β appears to be the most
important
 TGF-β is produced by most of the cells in granulation tissue & appears to be
highly related to
o Fibroblast migration & proliferation
o Increased synthesis of collagen & fibronectin
o Decreased degradation of the ECM
ECM Deposition
 Associated with both collagen accumulation and degradation
 Tissue remodeling
o Transition from granulation tissue to a scar (dense fibrosis), involves
transition in the composition of the ECM and matrix metalloproteinases
(MM): What stimulates, inhibits, or activates them?
o MM are associated with zinc ions and are enzymes
o The above should be distinguished from MBMM
o MM are rapidly inhibited by TIMP
 The brain has astroglial proliferation instead of scarring.
 Steroids decrease the inflammatory response so they retard wound healing.
 A cell can be inhibited typically by TGF- β or by steroids.
 Cell stimulation
o Stimulated by PDGF, EGF, IL-1/TNF
o Elaborates procollagenases or prostromelysins—MMs that are enzymes
associated with remodeling
o These are then activated by plasmin to yield collagenases or
stromelysins
o At some point, must stop this chain to stop the remodeling. So, there’s
tissue inhibitor to stop the MMs.
Wound healing
 Complex but orderly process
 Induction, acute inflammation
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 6 of 8
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Regeneration (parenchymal cells) Parenchyma is the substance of an organ
on the macroscopic level. The book uses it microscopically as the epithelial
components of an organ.
 Migration & proliferation
 Renewed synthesis, ECM
 Remodeling
 Collagenization; increasing wound strength
G. Healing by 1st intention
 Death of a certain # of epithelial cells & CT cells
 Disruptions of epithelial BM continuity
 Narrow space immediately fills with clotted blood & fibrin; dehydration
forms the scab
 Within 24 hours: polys
 Within 24 – 48 hours: cut edges thicken due to proliferation of basal cells &
spurs of epithelial cells from the edges migrate and grow along the cut
margins of the dermis.
 Thin, small lesions that are sometimes sutured
H. Healing by 2nd intention
 More extensive loss of cells and tissues; large defects
 Abundant granulation tissue
 Large areas
 Differs from 1st intention
o More intense inflammation
o Contraction at myofibroblasts
o You have a LOT more tissue contraction to minimize the destroyed
area. This may result in cosmetically displeasing results, especially if
sutures become infected.
 Primary or secondary intention healing depends upon the nature of the
wound
 Contracture—a gross lesion where an entire structure has been disrupted. In
the process of contraction, it’s lost its ability to function. Example:
Dupuytren contracture which occurs from an injury to the flexor tendons to
the finger leaving the fingers pulled into the hand and unable to grasp items.
I. Wound strength **
 A healed wound returns to maximum strength in about 3 months.
 However, some never regain full strength.
 Believe that fractured bones return to full strength.
 Know from which molecular elements (and from what features of those)
that wound strength is derived.
J. Summary
 All these processes overlap.
 Wound contraction is the last to occur and happens with 2nd intention
healing.
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 7 of 8
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Prototype of tissue repair
o Early phase—inflammation
o Fibroplasias
o Tissue remodeling
o Scarring
o The amazingly precise & 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 (how much tension is on the wound edges, especially
over a bony prominence), including forces generated by changes in cell
shape.
VII. Factors that influence wound healing
**tissue repair may be greatly influenced by a significant number of known and
some unknown influences
 Infection is the single most important factor in a non-healing injury.
A. Local Host Factors
 Infections
 Mechanical factors—depend on location of injury
 Foreign bodies—can become impacted and stimulate infection if not
removed
 Size, location, and type of wound
B. Systemic
 Nutrition
 Metabolic status/disease—diabetes is the poster child for this one
 Circulatory status
 Hormonal influences
VII. **Pathologic aspects of wound repair
A. Deficient scar formation
 Inadequate formation of granulation tissue
 Wound dehiscence
 Ulceration (poor vascularity or peripheral neuropathy seen in diabetics)
B. Excessive formation of the repair components
 Keloid
 Hypertrophic scar—much like a keloid, but has small differences
 Exuberant granulation tissue formation = proud flesh
 Aggressive fibromatosis—these are between benign and malignant
o Can’t know what their biological activity will be.
o Can benign tumors kill you? YES! This does depend on their locations.
A schwannoma pressing on the brainstem can kill you if it’s not
removed.
MOD #39
Thurs, 05/01/03, 9am
Dr. Putthoff
Jennifer Uxer for Kelly Thurmon
Page 8 of 8
o Aggressive fibromatosis kill too, often when they get into organs
necessary for life and cannot be removed—called nodular fascitis in
adults.
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.
Answer this: How do the latter differ from the orderly progression of wound
healing?