1. Molecular and Cellular Basis of Disease (MCBD)

2. Cell Injury

3. Overview + Stress Normal Adapted cell Cell - Stress +Stress Injury
Reversibly
injured cell
Apoptosis
Irreversibly
Injured cell
Dead cell
Normal cell has relative narrow range of functions and structure
Limited changes in metabolism = homeostasis (increased Glc and TG metabolism in active contracting muscle)
Stress = demands in excess of normal homeostatic changes leads to adaptations
If stress exceeds adaptive response of cell - injury
In addition, a variety of agents can directly injure cells (ie CN, , Hg, pH, temp, etc)
Necrosis
Overview

15. Normal
cell
+ Stress
Adapted
Cell
- Stress
Cellular adaptation

16. Increased/decreased workload
Normal
cell
+Stress
Adapted
Cell
- Stress
Stress = ?
Increased/decreased workload
* skeletal muscle and body building
* cardiac muscle and hypertension
* skeletal muscle disuse (limb immobilization)
Increased/decreased stimulation
* estrogenic stimulation of uterus in pregnancy
* estrogen/prolactin stimulation of breast (lactation)
* denervation of muscle

17. Cellular adaptations to stress 1. Hyperplasia (more cells)
Adapted
Cell
Cellular adaptations to stress
1. Hyperplasia (more cells)
2. Hypertrophy (bigger cells)
3. Atrophy (smaller cells)
4. Metaplasia (different type of cells)

18. 1. Hyperplasia (more cells) 1. Physiologic 2. Pathologic
* Hormonal (breast/uterus in pregnancy)
* Compensatory (liver after partial hepatectomy)
2. Pathologic
Excessive hormone/GF stimulation of target tissue
* Endometrial hyperplasia (x’s estrogen)
* Benign prostatic hyperplasia (x’s androgens)
* Connective tissue cells in wound healing
Hormonal: Breast at puberty; breast and uterus during pregnancy
Compensatory: regeneration of liver after partial hepatectomy
NB; hyperplasia regresses if stim removed; difference with cancer

19. Thyroid hyperplasia
Lft: normal thyroid gland: rings of epithelial cells surrounding colloid. Rt: hyperplasia/hypertrophy of Graves d; note epithelial projections into colloid.

20. Hyperplasia (Mechanism) Cell proliferation
via increased production of TRANSCRIPTION FACTORS
due to
* Increased production of GF
* Increased levels of GF receptors
* Activation of intracellular signaling
Results in larger organ

21. 2. Hypertrophy (larger cells)
Adapted
Cell
2. Hypertrophy (larger cells)
* Not due to swelling
* Increased synthesis of structural components
* Results in larger organ
* May occur with hyperplasia
Hypertrophy

22. Hypertrophy
Comments
* Often involves switch from adult to fetal/neonatal forms i.e. a-myosin heavy chain  b-myosin heavy chain
* Limited (can only increase so much)

23. Hypertrophy (Heart)
Middle = normal heart; left = hypertrophied heart due to hypertension; rt = dilated heart due to inability to adapt to continued stress

24. Hypertrophy of uterus
Physiologic Hypertrophy: A: rt = normal uterus, left = gravid uterus; B: left: small, spindle-shaped smooth muscle cells; rt: larger, more rounded cells of gravid uterus

25. Normal
Hypertrophied
Cardiac smooth muscle hypertrophy

26. Hypertrophy (Mechanisms)
Increased synthesis of structural proteins via
Transcription factors (i. e. c-fos and c-jun)
Growth factors (TGF-b, IGF-1, FGF)
Vasoactive agents (endothelien-1, AII)

27. Figure 1-4 Changes in the expression of selected genes and proteins during myocardial hypertrophy.

28. 3. Atrophy (smaller cells)
1. Physiologic
During development: i.e. notochord; thyroglossal duct
2. Pathologic (local or generalized) via
* disuse * Loss of endocrine stimulation
* denervation * Aging
* ischemia * Pressure
* Nutrition
Diminished function but not dead.

29. Kidney: atrophy via renal artery stenosis
Kidney: atrophy via renal artery stenosis. NB: decrease in cortex (most metabolically active cells)

30. Normal
Atrophied
Brain atrophy

31. Muscle fiber atrophy. The number of cells is the same as before the atrophy occurred, but the size of some fibers is reduced. This is a response to injury by "downsizing" to conserve the cell. In this case, innervation of the small fibers in the center was lost. This is a trichrome stain.

32. Atrophy (Mechanism) Reduction in structural components
Decreased number of mito, myofilaments, ER via
proteolysis (lysosomal proteases; ubiquitin-proteosome system)
Increase in number of autophagic vacuoles
Residual bodies (i.e. lipofuscin  brown atrophy)
NB: diminished function but not dead
Glucocorticoids, thyroid hormone and TNF stim proteosome-mediated protein degradation; insulin opposes

33. 4. Metaplasia **One adult cell type replaces another** Reversible
Columnar to squamous epithelium (most common epithelial type of metaplasia)
Chronic irritation i.e. (in trachea and bronchi of smokers)
Vit A deficiency squamous metaplasia in respiratory epithelium
May be some loss of function
May predispose to maligancy
Squamous thought to be more durable cell type
Squamous epithelium don’t  mucus
Acid reflux  col to squamous metaplasia (Barrett esophagus)
Connective tissue metaplasia = formation of bone, cart, or adipose tissue in tissues that normally don’t contain them

34. Photomicrograph of the trachea from a smoker. Note that the columnar
ciliated epithelium has been replaced by squamous epithelium.

35. Photomicrograph of the junction of normal epithelium (1) with hyperplastic
transitional epithelium (2).

36. Metaplasia (Mechanism)
Reprogramming
1. of stem cells present in normal tissues
2. of undifferentiated mesenchymal cells in connective tissue
Mediated by signals from
cytokines, GF or ECM
Leading to induction of specific transcription factors

37. Metaplasia versus Dysplasia
1. Dysplasia is a pathological term used to refer to an irregularity that hinders cell maturation within a particular tissue whereas Metaplasia is the process of the reversible substitution of a distinct kind of cell with another mature cell of the similar distinct kind. 2. Dysplasia is cancerous whereas Metaplasia is non-cancerous. 3. Metaplasia can be stopped by removing the abnormal stimulus, but Dysplasia is a non-reversible process.