Pathology 425 & 426 Lecture: Cell Injury and Adaptation

Richard Anderson, MD UIC College of Medicine
Partner, Associated Pathology Consultants, S.C.

Edward Hospital & Elmhurst Memorial Hospital
Phone: (630) 527-3608

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Lecture Goals:

I.          Give examples of reversible and nonreversible cellular injury and explain

            the morphologic and ultrastructural changes associated with both

II.        Examine the differences between the major adaptive reactions to persistent

            cellular stress

III.       Give examples of and ensure understanding of the differences between

            metaplasia and dysplasia

IV.       Gain an understanding of the pathogenesis of necrosis

V.         Give visual examples of cellular apoptosis and explain some of the genetic

            controls over "programmed cell death"

Definition of Terms:


Pathology                                           The study of structural and functional abnormalities that are

                                                            expressed as diseases of organs and systems.


Cellular adaptation                             An alteration of the homeostatic cellular steady state in which

                                                            the cell remains viable


Cellular injury                                               A sequence of events which occur when the adaptive ability of

                                                            a cell is exceeded; injury may be reversible up to a certain

                                                            point, though if the stimulus persists, irreversible injury may



Hydropic swelling (degeneration)                  An increase in cell volume, due to an increase H2O content;

                                                            such degeneration is acute and usually reversible


Atrophy                                               Decrease in size and function of a cell often leading to a

                                                            decrease size/volume of the organ

Hypertrophy                                        Increase in the size of a cell accompanied by an

augmented functional capacity, leading to an increase

in size/volume of the organ


Hyperplasia                                         In increase in the number of cells in an organ, often leading

                                                            to an increase in organ size/volume


Metaplasia                                          Reversible change in which one cell type is replaced by

                                                            another, which is usually more apt to withstand stress


Dysplasia                                            A preneoplastic condition resulting in an alteration in the size,

shape and organization of the cellular components of a tissue


Necrosis                                              The sum of irreversible biochemical and structural changes

                                                            resulting in cell death; necrosis is an accidental passive

                                                            process and has no role in normal tissue physiology; there

                                                            is an associated inflammatory response


Apoptosis                                           Genetically determined and biologically meaningful process

                                                            in which cells that are immunologically reactive against self,

                                                            infected or genetically damaged are removed to protect the

                                                            host; there is phagocytosis though no associated inflammatory


Reversible Cellular Injury:

Hydropic swelling is an increase in cell volume due to water influx.  The cell increases in size.  The cytoplasm is pale and expanded while the central nucleus is unremarkable.  Such degeneration is the result of acute, reversible injury which may be the result of:

       microbial agents:  viruses and bacteria

       physical agents:  heat, cold, trauma, radiation

       chemical agents:  drugs, poisons

       immune injury:  atopic (allergic) reaction, autoimmunity

       deficiency of nutrients:  ischemia, hypoxia

       metabolic changes:  acidosis, hormonal excess or deficiency


By electron microscopy, there are a number of changes which take place:

       distention of cisternae of endoplasmic reticulum

       detachment of ribosomes from rER with increase in free cytoplasmic ribosomes

       swelling of mitochondria

       formation of blebs in the plasma membrane

       segregation of fibrillar and granular components of the nucleolus

The most important thing to remember is that after withdrawal of the stress, theses changes are completely reversible.

Major Adaptive Reactions to Persistent Stress:






       intracellular deposits


Atrophy is a decrease in the size and function of a cell.  Causes and examples of atrophy include:

            1.  Reduced functional demand:       skeletal muscle due to persistent immobilization, disuse

            2.  Ischemia:       Unilateral renal artery stenosis (Goldblatt kidney)

            3.  Insufficient nutrients:   malnutrition, cachexia

            4.  Interruption of trophic signals:  menopause with cystic atrophy of the endometrium; Addison's disease

            5.  Persistent cellular injury:          end-stage renal failure; villous atrophy with celiac sprue

            6.  Aging:          decrease in size of organs, e.g., senile ovarian atrophy


Hypertrophy is an increase in the size of a cell and organ.  Causes and examples of hypertrophy include:

            1.  Physiologic hormonal hypertrophy:        breast hypertrophy in preparation for lactation

            2.  Pathologic hormonal hypertrophy:         colloid nodular disease (toxic nodular goiter) of the thyroid due to increase TSH

            3.  Increased functional demand:      myocardial hypertrophy

            4.  Persistent cellular damage:        alcoholic hepatitis


Hyperplasia is an increase in the number of cells in an organ, which usually results in an increase in size of the organ.  Causes and examples of hyperplasia include:

            1.  Physiologic hormonal hyperplasia:         increase in endometrial stromal and glandular elements during proliferative phase of menstural cycle

            2.  Pathologic hormonal hyperplasia:          gynecomastia

            3.  Increased functional demand:      erythroid hyperplasia of bone marrow in response to anemia

            4.  Persistent cellular injury:          pseudoepitheliomatous hyperplasia of skin overlying an ulcer site


Metaplasia is a reversible change in which one cell type is replaced by another, which is usually more apt to withstand stress.  Though most of the time, metaplasia is a harmless process (e.g., squamous metaplasia of the cervix), there are certain types of metaplasia (Barrett's esophagus incomplete intestinal metaplasia) which carry an increased risk of malignant transformation.  Metaplasia is under genetic control.  An example of this is the differential expression of mucin genes (MUC1-MUC7) in normal respiratory epithelium, metaplastic respiratory epithelium and malignant epidermoid carcinoma of the respiratory tract (Copin MC, et al.  2000. Int J Cancer; 86:162-168.)  Metaplasia is usually fully reversible.  Examples of metaplasia include:

            1.  Endocervical squamous metaplasia

            2.  Barrett's specialized intestinal metaplasia.


Cellular dysplasia refers to an alteration in the size, shape and organization of the cellular components of a tissue.  Dysplasia is a preneoplastic condition.  In dysplasia, there is increased cell proliferation accompanied by abnormalities in cell size, configuration and orientation.  In mucinous epithelium (e.g., colon) the following changes may be observed in dysplastic epithelium:

       reduced or absent mucus secretion

       increase N:C ratio

       loss of nuclear polarity

       cellular stratification

       increase in mitotic activity

       architectural distortion of glands

As one would expect, dysplasia is also under genetic control.  In adenomatous polyps (tubular adenomata) of the colon, aneuploidy can be detected in about 35% of cases, p53 expression is found in a minority of cases and bcl-2 immunoreactivity is present in virtually all cases.  Fearon and Vogelstein (1990. Cell; 61:759-767) have proposed a genetic model for transformation of normal colonic epithelium to dysplastic epithelium to carcinoma (the so-called adenoma-carcinoma sequence).  Examples of dysplasia include:

            1.  Adenomatous colonic polyp

            2.  Cervical intraepithelial neoplasia

            3.  Barrett's specialized intestinal metaplasia with dysplasia

Intracellular storage:

Intracellular storage is a normal cellular function.  However, abnormal or excessive accumulations are seen in certain disease states as well as a consequence of inborn errors in metabolism.  Examples of intracellular storage include:

            1.  Alcoholic and non-alcoholic steatohepatitis:         excessive storage of fat in the form of

triglycerides occurs when hepatic

metabolism of lipids is disturbed or when

delivery of free fatty acids to the liver is

increased as in diabetes, obesity and

corticosteroid usage

            2.  Glycogen storage disease:         at least 10 distinct inherited disorders characterized by

accumulation of glycogen in the liver, skeletal muscle and heart secondary to specific enzyme defects in the metabolism

of glycogen

            3.  Lysosomal storage disease:       Enzymatic defects in the metabolism of complex lipids and

                                                            mucopolysaccharides.  The most common lysosomal storage

                                                            disease is type 1 Gaucher disease.  This disorder is

                                                            non-neuronopathic (though other neuronopathic forms exist).

                                                            The underlying abnormality is a deficiency in

glucocerebrosidase.  This has been mapped to a variety of

mutations involving the b-glucosidase gene (1q21).  Affected

individuals (principally Ashkenazi Jews) live a normal life

span though experience deposition of lipid-laden macrophages

in the bone marrow, spleen, liver, lymph nodes and lung.

            4.  Hemosiderosis and Hemochromatosis:     When the total body iron increases, excess iron is

stored in the form of ferritin and hemosiderin.  The

progressive accumulation of hemosiderin is referred

to as hemosiderosis.  In the liver, this is akin to

increased iron sinusoidal Kupffer cells.  The intracellular iron does not injure the cell.  On the other hand, in hereditary hemochromatosis there is a genetic defect (HHC gene on chromosome 6) resulting in an increase in duodenal iron absorption leading to toxic deposition in the liver, heart and pancreas.

Irreversible Cell Injury:


Necrosis refers to the sum of irreversible biochemical and structural changes resulting in cell death.  It is an accidental passive process, which has no role in normal tissue physiology.  There is an associated inflammatory response.  Classic morphologies and examples of necrosis include:

            1.  Coagulative necrosis:               This is most common type of necrosis seen under the

microscope.  The nucleus initially becomes small and

darkly basophilic (pyknosis) followed by disintegration

(karyorrhexis) and eventual loss of staining (karyolysis).

The cytoplasm is densely eosinophilic. 

EX:       acute myocardial infarction

            2.  Liquefactive necrosis:               Essentially an abcess where the infiltration of neutrophils

                                                            precludes complete coagulative necrosis.

                                                            EX:       wet gangrene of soft tissues as in diabetes

            3.  Fat necrosis:              As inferred, usually occurs in adipose tissue as a consequence of

                                                trauma.  There is significant macrophage deposition.  Fat necrosis

                                                also occurs in the pancreas due to release of pancreatic enzymes.

                                                EX:       mammary fat necrosis at the site of previous biopsy

            4.  Casseous necrosis:      Classically associated with tuberculosis and other necrotizing

                                                granulomatous disorders. 

                                                EX:       pulmonary tuberculosis

            5.  Fibrinoid necrosis:      Used to refer to necrosis of vascular walls in which the insudation of

                                                plasma proteins which stain intensely eosinophilic.

EX:       temporal (giant cell) arteritis
The pathogenesis of necrosis:
There are 3 main cellular characteristics of necrosis:


       plasma membrane damage results in an inability to maintain ion balance
       increase in intracellular Ca++
       loss of mitochondrial function


Reperfusion injury:
This is a somewhat paradoxical response involving the damaging effect of oxygen to a cell that has "suffered" irreversible cell injury.  Clinically, this is an extremely important event which occurs during myocardial infarction as well as cardioplegic arrest during cardiac surgery.  Principle mediators of this phenomenon are oxygen radicals (O2-, H2O2, -OH) and neutrophils.  Reperfusion of postischemic tissue is accompanied by generation of large amounts of oxygen radicals formed by a number of mechanisms:
       mitochondrial respiration
       xanthine oxidase activity
       byproduct of neutrophil activation
These oxygen radicals have the following effects:
       peroxidation of unsaturated lipids in the plasma membrane resulting in an unstable membrane
       oxidation of glutathione (production of disulfide bond) as well as other sulfhydryl groups leading to protein dysfunction
       inhibition of oxidative phosphorylation in mitochondria
       induce binding of neutrophils to intact vessels by ICAM-1 and CD18 interaction
       stimulated the production of PAF (see lecture on inflammation) by endothelial cells
       induce release of proinflammatory cytokines (e.g., TNF-a: see lecture on inflammation)
***for a concise review of reperfusion injury, see: 
Ambrosio G, Tritto I.  1999. Reperfusion injury:  experimental evidence and clinicalapplications.  Am Heart J; 138:S69-S75.
Apoptosis is a genetically determined and biologically meaningful process in which cells that are immunologically reactive against self, infected or genetically damaged are removed to protect the host.  There is phagocytosis though no associated inflammatory response.  Morphologically, there is nuclear condensation and fragmentation.  The surface membrane becomes irregular and the cell fragments into membrane-bound bodies which may or may not contain nuclear material.  These are phagocytized.  Apoptosis can be triggered by a variety of extrinsic and intrinsic signals.  It appears to be carried out through the activation of endogenous proteases which disrupt the integrity of the cytoskeleton and endonucleases which degrade nuclear DNA.  The key feature of apoptosis is that the plasma membrane remains intact. 
Apoptosis is genetically regulated.  Early experiments to identify genes that regulated cell death during the development of the nematode Caenorhabditis elegans led to the discovery of 3 genes (CED-9, CED-4 and CED-3).  It was found that if CED-9 was mutated, apoptosis was prevented.  Mammalian homologs for all three genes have been found.  When CED-9 was cloned, it was found to be related to the mammalian oncogene, bcl-2.  This gene is present on chromosome 18 and was originally identified because of its involvement in a 14:18 translocation present in 85% of follicular non-Hodgkin's lymphoma.  CED-3 is an endogenous protease.  When this was cloned, it was also found to have a similar mammalian counterpart called, interleukin 1b converting enzyme (ICE).  This was the first member of the mammalian caspase system identified.  These caspases are intracellular cysteine proteases that have the novel ability to cleave proteins after an aspartate residue (hence the name).  Twelve members of the caspase family have been identified (termed 1-12); caspase 8 (AKA, FLICEsee below) is hypothesized to be essential for apoptosis.   
The rate at which apoptotic signaling events initiate or amplify caspase activity is regulated by proteins of the Bcl-2 family.  A number of Bcl-2-related proteins have been identified (at least 16 in humans).  Paradoxically, some of these proteins have been shown to promote apoptosis (Bax, Bak, Bok/Mtd) whereas others suppress apoptosis (Bcl-2, Bcl-XL).
Apoptosis may also be initiated through extrinsic ligands which bind to cell surface receptors.  One of the best characterized is a member of the tumor necrosis factor (TNF) family, Fas.  Fas is also known as APO-1 or CD95.  Fas is the membrane receptor for Fas ligand (FasL).  Fas is ubiquitously expressed in various tissues.  FasL on the other hand, is predominantly expressed in activated T lymphocytes, NK cells and macrophages.  When FasL binds Fas, an intracytoplasmic protein adaptor (the Fas-associated death domain or FADD) is recruited.  This binding eventually leads to activation of one of the caspases referred to as caspase 8 or FLICE for FADD-like ICE.  There have been a number of well written reviews of this process (if you are interested, see:  Nagata S.  1997.  Apoptosis by death factor. Cell; 88: 355-365.
In addition to ligand/receptor mediated induction of apoptosis, a variety of agents can induce apoptosis through lesser understood pathways.  One emerging model has as its critical components caspase 9 and a protein termed Apaf1.  In this model, cytochrome c is released from a mitochondria under stress.  Cytochrome c would then associate with a complex of Apaf1 and caspase 9, resulting in the activation of caspase 9.  This would lead to the activation of caspase 3 and the initiation of apoptosis.  The nematode gene, CED-4 is structurally similar to its mammalian counterpart, Apaf1.
Therapeutic opportunities for the treatment of certain types of cancer are arising with further study of apoptosis regulatory genes.  Follicular lymphoma is an example in which the neoplastic cell expansion is primarily caused by failed apoptosis rather than by rapid cell division.  In addition to its involvement in a wide variety of hematologic malignancies, the bcl-2 oncogene has also been associated with prostate, lung, melanoma, breast and other solid organ malignancies.  The Bcl-2 family proteins have also been implicated in resistance to cancer therapies, which have the induction of the apoptotic pathway as their common basis.  In fact, there is now abundant evidence that Bcl-2 may act as a multi-drug resistance protein that prevents or markedly delays apoptosis induction by radiation therapy and a variety of anti-cancer chemotherapies.  The p53 tumor suppressor gene may play an important role in this regard.  Wild-type p53 induces apoptosis following DNA damage.  Bax is transcriptionally activated by wild type p53 binding.  The overexpression of Bax (and other pro-apoptotic members of the Bcl-2 family) renders tumor cells MORE sensitive to many chemotherapeutic agents.  Conversely, ablating Bax expression reduces drug-induced apoptosis.  In addition, Bcl-2 appears to have an inhibitory effect on p53, impairing nuclear import of p53 following genetic damage, thus, inhibiting apoptosis.  (see:  GutiJrrez-Puente Y, et al.  2002. Bcl-s-related antisense therapy. Semin Oncol 29(suppl 11):71-76.)     
Though apoptosis is an important mechanism used by the body to eliminate damaged cells, dysregulated apoptosis has been implicated in many human diseases such as cancer, neurodegenerative diseases and ischemic heart disease.  
Pertinent Internet Sites:
***The following sites contain information for introductory general and systemic pathology lectures.
            This site is out of Cornell University Medical Center.  It is very complete, though a bit dry to
            say the least.
            An excellent site with full lectures and slides.
            This is a huge site with a lot of information.  It is maintained by one "unique" individual.

Reading Assignment:
Robbins, Pathologic Basis of Disease, 6th edition:



Reversible cellular injury


Atrophy, hypertrophy, hyperplasia, metaplasia, intracellular deposits





4-11, 15-18

Reperfusion injury


Chemical injury