Apoptosis: Mechanisms and Roles in Pathology

doi:10.1016/B978-0-12-364932-4.50010-1

International Review of Experimental Pathology

Volume 32, 1991, Pages 223-254

https://doi.org/10.1016/B978-0-12-364932-4.50010-1 Get rights and content

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This chapter discusses the mechanisms and roles of apoptosis in pathology. Necrosis differs from apoptosis in structure, mechanism, and sequelae. Structurally, necrotic cells show critically damaged organelles, ruptured plasma membranes, and dispersal of cytoplasmic elements into the extracellular space. The mechanisms are various, but do not depend upon continuing synthetic activity. There is no evidence that specific signaling pathways are involved. There is breakdown of membrane homeostasis and net flow of water into the necrotic cell, whose density falls. Intracellular calcium rises uncontrollably to equilibriate with the millomolar concentrations in the extracellular space. The process results in an acute inflammatory reaction, triggered by complement-activating factors emanating from mitochondria that have escaped from the damaged cell. Alternatively, leukotrienes and other arachidonate chemotaxins can be generated from partially- degraded cell membranes. The arrival of neutrophil polymorphs permits digestion and phagocytosis of the constituents of the necrotic cells, but brings with it the risk of further tissue damage.

References (142)

E.S. Alnemri et al.
J. Biol. Chem.
(1989)
S.K. Chapes et al.
Cell. Immunol.
(1983)
M.M. Compton et al.
J. Biol. Chem.
(1987)
A.R. Currie et al.
Lancet
(1962)
K.-M. Debatin et al.
Lancet
(1990)
K. Drickamer
J. Biol. Chem.
(1988)
E. Duvall et al.
Immunol. Today
(1986)
L. Fesus et al.
FEBS Lett.
(1987)
L. Fesus et al.
FEBS Lett.
(1989)
B.D. Halligan et al.
J. Biol. Chem.
(1985)

C. Haslett et al.

Curr. Opin. Immunol.

(1989)

R.O. Hynes

Cell

(1987)

R. Ishida et al.

Biochem. Biophys. Res. Commun.

(1974)

L.F. Liu et al.

Cell

(1980)

E. Martz et al.

Immunol. Today

(1989)

D.J. McConkey et al.

Arch. Biochem. Biophys.

(1989)

D.J. McConkey et al.

J. Biol. Chem.

(1989)

D.R. Phillips et al.

Blood

(1988)

M. Skalka et al.

FEBS Lett.

(1976)

N. Allbritton et al.

J. Exp. Med.

(1988)

M.J. Arends et al.

Am. J. Pathol.

(1990)

G. Ashwell et al.

Annu. Rev. Biochem.

(1982)

F.R. Balkwill

Br. Med. Bull.

(1989)

E.A. Barker et al.

Am. J. Pathol.

(1973)

G.D. Baxter et al.

J. Pathol.

(1989)

G. Berke

Prog. Allergy

(1980)

I.D. Bowen et al.

W. Bursch et al.

Carcinogenesis

(1984)

R. Buttyan et al.

Mol. Endocrinol.

(1988)

K.-C. Chow et al.

Mol. Cell Biol.

(1987)

W. Clark et al.

Immunol. Rev.

(1988)

J.J. Cohen et al.

J. Immunol.

(1984)

C. Denzlinger et al.

Science

(1985)

I. Dransfield et al.

Immunol. Rev.

(1990)

R.C. Duke et al.

Lymphokine Res.

(1986)

R.C. Duke et al.

Proc. Natl. Acad. Sci. U.S.A.

(1983)

E. Duvall et al.

Immunology

(1985)

T.A. Dykes et al.

Clin. Res.

(1987)

M.E. Elmes

J. Pathol.

(1977)

D.J.P. Ferguson et al.

Virchows Arch. A: Pathol. Anat. Histol.

(1981)

D.J.P. Ferguson et al.

Br. J. Cancer

(1981)

I.V. Filippovich et al.

Int. J. Radiat. Biol.

(1982)

J.T. Finch et al.

Proc. Natl. Acad. Sci. U.S.A.

(1976)

D. Flieger et al.

Int. J. Cancer

(1989)

G.C. Gobe et al.

Int. J. Radiat. Biol.

(1988)

P. Golstein

Nature (London)

(1987)

H. Green

Harvey Lect.

(1980)

P. Gullino

Prog. Cancer Res. Ther.

(1980)

A.H. Handyside et al.

Wilhelm Roux's Arch. Dev. Biol.

(1986)

D.J. Harrison

Histopathology

(1988)

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Apoptosis: Mechanisms and Roles in Pathology

Publisher Summary

J. Biol. Chem.

Cell. Immunol.

J. Biol. Chem.

Lancet

Lancet

J. Biol. Chem.

Immunol. Today

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Curr. Opin. Immunol.

Cell

Biochem. Biophys. Res. Commun.

Cell

Immunol. Today

Arch. Biochem. Biophys.

J. Biol. Chem.

Blood

FEBS Lett.

J. Exp. Med.

Am. J. Pathol.

Annu. Rev. Biochem.

Br. Med. Bull.

Am. J. Pathol.

J. Pathol.

Prog. Allergy

Carcinogenesis

Mol. Endocrinol.

Mol. Cell Biol.

Immunol. Rev.

J. Immunol.

Science

Immunol. Rev.

Lymphokine Res.

Proc. Natl. Acad. Sci. U.S.A.

Immunology

Clin. Res.

J. Pathol.

Virchows Arch. A: Pathol. Anat. Histol.

Br. J. Cancer

Int. J. Radiat. Biol.

Proc. Natl. Acad. Sci. U.S.A.

Int. J. Cancer

Int. J. Radiat. Biol.

Nature (London)

Harvey Lect.

Prog. Cancer Res. Ther.

Wilhelm Roux's Arch. Dev. Biol.

Histopathology