Ganong's Review of Medical Physiology, 23rd Edition

76 SECTION ICellular & Molecular Basis for Medical Physiology

is characterized by redness, swelling, tenderness, and pain.
Elsewhere, it is a key component of asthma, ulcerative colitis,
and many other diseases.
Evidence is accumulating that a transcription factor,
nuclear factor-κB, plays a key role in the inflammatory
response. NF-κB is a heterodimer that normally exists in the
cytoplasm of cells bound to IκBα, which renders it inactive.
Stimuli such as cytokines, viruses, and oxidants separate NF-

κB from IκBα, which is then degraded. NF-κB moves to the
nucleus, where it binds to the DNA of the genes for numerous
inflammatory mediators, resulting in their increased produc-
tion and secretion. Glucocorticoids inhibit the activation of

NF-κB by increasing the production of IκBα, and this is prob-

ably the main basis of their anti-inflammatory action (see

Chapter 22).

SYSTEMIC RESPONSE TO INJURY

Cytokines produced in response to inflammation and other

injuries also produce systemic responses. These include alter-

ations in plasma acute phase proteins, defined as proteins

whose concentration is increased or decreased by at least 25%

following injury. Many of the proteins are of hepatic origin. A

number of them are shown in Figure 3–14. The causes of the

changes in concentration are incompletely understood, but it

can be said that many of the changes make homeostatic sense.

Thus, for example, an increase in C-reactive protein activates

monocytes and causes further production of cytokines. Other

changes that occur in response to injury include somnolence,

negative nitrogen balance, and fever.

WOUND HEALING

When tissue is damaged, platelets adhere to exposed matrix via

integrins that bind to collagen and laminin (Figure 3–13).

Blood coagulation produces thrombin, which promotes platelet

aggregation and granule release. The platelet granules generate

an inflammatory response. White blood cells are attracted by

selectins and bind to integrins on endothelial cells, leading to

their extravasation through the blood vessel walls. Cytokines re-

leased by the white blood cells and platelets up-regulate inte-

grins on macrophages, which migrate to the area of injury, and

on fibroblasts and epithelial cells, which mediate wound healing

FIGURE 3–11 Action of cyclosporine (CsA) and tacrolimus
(TCL) in lymphocytes. BP, binding protein; CAM, calmodulin.

T cell receptor

Ca^2 +

CAM

Calcineurin

TCLBP

CsABP

P

NF-AT

IL-2 gene

activation

Nucleus

FIGURE 3–12 Sites of congenital blockade of B and T lymphocyte maturation in various immunodeficiency states. SCID, severe
combined immune deficiency. (Modified from Rosen FS, Cooper MD, Wedgwood RJP: The primary immunodeficiencies. N Engl J Med 1995;333:431.)

Pluripotent

stem cell

Lymphoid

progenitor

Autosomal

recessive SCID

BONE

MARROW

pre-B cell

THYMUS

Immature

T cell

X-linked SCID

X-linked

agamma-

globulinemia

B cell

Hyper-IgM

syndrome

IgM IgG IgA IgE

MHC class I

deficiency

MHC class II

deficiency

CD8

cell

CD4

cell