Physical factors alone do not only include for high degree of resistance shown by

skin and mucous membranes against microbial invasion. Certain chemical factors also
play important roles.

Sebaceous (oil) glands of the skin produce an oily substance called sebum that
prevents hair from drying and becoming brittle. Sebum also forms a protective film
over the surface of the skin. One of the components of sebum is unsaturated fatty
acids, which inhibit the growth of certain pathogenic bacteria and fungi. The low pH
of the skin, between 3 and 5 is cause din part by the secretion of fatty acids and lactic
acid. The skin’s acidity is probably probably discourages the growth of the many
other microorganisms.

Bacteria that live commensally on the skin decompose discarded skin cells, and the
resultant organic molecules end products of their metabolism produce body odor.
Certain bacteria commonly found on the skin metabolize sebum, and this metabolism
forms these fatty acids that cause the inflammatory response associated with acne.
Isotretinoin, a derivative of vitamin A that prevents sebum formation , is a treatment
for a very severe type of acne called cystic acne.
The sweat glands of the skin produce perspiration, which helps maintain body
temperature, eliminates certain wastes, and flushes from the surface of the skin.
Perspiration also contains lysozyme, an enzyme capable of breaking down cell walls
of gram positive bacteria to a lesser extend, gram negative bacteria. Specifically,
lysozyme breaks down chemical bonds on peptidoglycan which destroys cell walls.
Lysozyme is also found in tears, saliva, tissue fluids, and urine where it exhibits it’s
antimicrobial activity. Alexander Fleming was studying lysozyme in1928 when he
accidentally discovered the antimicrobial effects of penicillin.

Earwax, besides serving as a physical barrie also functions as a chemical protectant.

It is a mixture of secretions from glands producing earwax as well as from the
sebaceous glands, which produce sebum. The secretions are rich in fatty acids, giving
the ear canal a low pH between 3 and 5 which inhibits the growth of pathogenic
microbes. Earwax also contains many dead cells from the lining of the ear canal.
 Saliva contains not only the enzyme salivary amylase that digests starch but also a
number of substances that inhibit microbial growth. These include lysozyme, urea,
and uric acid. The slightly acidic pH of saliva (6.55-6.85) also inhibits some
microbes. Saliva aditionally contains an antibody (lgA) that prevents attachment of
microbes so that they can penetrate mucous membranes.

Gastric juice is produced by the glands of the stomach. It is a mixture of

hydrochloric acid, enzyme and mucus. The very high acidity of gastric juice (pH 1.2-
3.0) is sufficient to destroy bacteria and most bacterial toxins except those of
Clostridium botulinum and Staphylococcus aureus. However, many enteric
pathogenic particles are protected by food particles and can enter the intestines via the
gastrointestinal tract. In contrast, Helicobacter pylori neutralizes stomach acid,
thereby allowing the bacterium to grow in the stomach. Its growth initiates an immune
response that results in gastritis and ulcers.

Vaginal secretions play a role in antibacterial activity in two ways. Glycogen

produced by vaginal epithelial cells is broken down into lactic acid by Lactobacillus
species. This creates an acidic pH ( 3-5) that inhibits microbes. Cervical mucus also
has some antimicrobial activity. Urine which in addition to containing lysozyme, has
an acidic average of 6 that inhibits microbes.

INFLAMMATION
Damage to the body’s tissues triggers a local defensive response called inflammation,
another component of the second line of defense. The damage can be caused by
microbial infection, physical agents (such as heat, radiant energy, electricity, or sharp
objects), or chemical agents (acids, bases, and gases). Certain signs and symptoms
that are associated with inflammation, which you can remember by thinking the
acronym PRISH:
Pain due to release of certain chemicals
Redness because more blood goes to the affected area
Immobility that results from local loss of function in severe inflammation
Swelling caused by an accumulation of fluids
Heat, which is also due to an increase in blood flow to the affected area
Inflammation has the following functions: (1) to destroy the injurious agent, if
possible, to remove its by-products from the body; (2) if destruction is not possible,
to limit the effects on the body by confining or walling off the injurious agent and its
by-products; (3) to repair or replace tissue damaged by the injurious agent or its by-
products.

Inflammation can also be classifiedas accute or chronic, depending on a number of

factors. In acute inflammation, the signs and symptoms develop rapidly and usually
lasts for a few days or even a few weeks.It is usually mild and self-limiting, and the
principal defensive cells are neutrophils. Examples of acute inflammation are sore
throat, appendicitis, cold or flu, bacterial pruemonia and a scratch on the skin. In
chronic inflammation, the signs and symptoms develop more slowly and can last for
up to several months or years. It is often severe and progressive, and the principal
defensive cells are monocytes and macrophages. Examples of chronic inflammation
are mononucleosis, peptic ulcers, tuberculosis, rheumatoid arthritis, and ulcerative
colitis( inflammatory bowel disease).

During the early stages of inflammation, microbial structure such as flagellin,

lipopolysachrides (LPS), and bacterial DNA stimulate the Toll-like receptors of
macrophages to produce cytokines, such as tumor necrosis factor alpha (TFN-α).
In response to TFN-α in the blood, the liver synthesizes a group of proteins called
acute-phase proteins; other acute phase proteins are present in the blood in an inactive
form and are converted to an active form during inflammation. Acute-phase proteins
induce both local and systemic responses and include proteins such as C-reactive
protein, mannose-binding lectin and several specialized proteins such as fibrinogen
for blood clotting and kinins for vasolidation.
All of the cells involved in inflammation have receptors for TFN-α and are activated
by it to produce more of their own TFN-α. This amplifies the inflammatory response.
Unfortunately, excessive production of TFN-α may lead to disorders such as
rheumatoid arthritis and Crohn’s disease. Monoclonal antibodies are used
therapeutically to treat such inflammatory disorders.

VASODILATION AND INCREASED PERMEABILITY OF BLOOD

VESSELS
Immediately following the tissue damage, blood vessels dilate (increase in diameter)
in the area of damage, and their permeability increases. Dilation of blood vessels
called vasodilation, is responsible for the redness(erythema) and heat associated with
inflammation.
Increased permeability permits defensive substances normally retained in the blood to
pas through the walls of the blood vessels and enter the injured area. The increase in
permeability, which permits fluid to move from the blood into the tissue spaces, is
responsible for the edema (accumulation of fluid) of inflammation. The pain of
inflammation can be caused by nerve damage, irritation by toxins, or the pressure of
edema.

1. Vasodilation and the increase in permeability of blood vessels are caused by a

number of chemicals released by damaged cells in response to injury. These
chemicals are called vasoactive mediators. One such substance is histamine, a
chemical present in many cells of the body, especially in mast cells in connective
tissue, circulating basophils, and blood platelets. Histamine is released in direct
response to the innjury of cells that contain it; it is also released in response to
stimulation by certain components of the complement system.
Phagocytic granulocytes attracted to the site of injury can also produce chemicals
that cause the release of histamine.
Kinins are another group of substances that cause vasodilation and increased
permeability of blood vessels. Kinins are present in blood plasma, and once arrived,
they play a role in the chemotaxis by attracting phagocytic granulocytes, chiefly
neutrophils, to the injured area.
Prostaglandins, substances released by damaged cells, intensify the effects of
histamine and kinins and help phagocytes move through capillary walls. Despite their
positive role in the inflammatory process, prostoglandins are also associated with the
pain related to inflammation. Leukotrienes are substances produced by mast cells
(cells especially numerous in the connective tissue of the skin and respiratory system,
and in the blood vessels) and basophils. Leukotrienes cause increased permeability of
blood vessels and help attach phagocytes to pathogens. Various components of the
complement system produced by the liver stimulate the release of histamine, attract
phagocytes, and promote phagocytosis.
Activated fixed macrophages also secrete cytokines, which bring about vasolidation
and increased permeability of blood vessels also help deliver clotting elements of
blood into the injured area.
2. The blood cloths that form around the site of activity prevent the microbe (or its
toxins) from spreading to other parts of the body.
3. As a result, there may be a localized collection of pus, a mixture of dead cells and
body fluids, in a cavity formed by the breakdown of body tissues. This focus of
infection is called an abscess. Common abscess include pustules and boils.

VASOACTIVE SOURCE EFFECT

MEDIATOR
Histamine Mast cells, basophils, and Vasodilation and increased
platelets permeability of blood
vessels
Kinins Blood plasma Chemotaxis by attracting
neutrophils
Prostaglandins Damaged cells Intensify the effects of
histamine and kinins and
help phagocytes move
through capillary walls
Leokotrienes Mast cells and Basophils Increase permeability of
blood vessels and help
attract phagocytes to
pathogens
Complement Blood plasma Stimulates release of
histamine, attracts
phagocytes and promotes
phagocytosis
Cytokines Fixed macrophages Vasodilation and increased
permeability of blood
vessels
Summary of Vasoactive Mediators of Inflammation
PHAGOCYTE MIGRATION AND PHAGOCYTOSIS
Generally, withn an hour after the process of inflammation is initiated, phagocytes
appear on the scene.
4. As the flow of the blood gradually decreases, phagocytes (both neutrophils and
monocytes) begin to stick to the inner surface of the endothilium (lining) of the blood
vessels. This sticking process in response to the local cytokines is called
margination. The cytokines alter the cellular adhesion molecules on cells lining
blood vessels, causing the phagocytes to stick at the site of inflammation.
(Margination is also involved in red bone marrow, where cytokines can release
phagocytes into circulation when they are needed.)
5. Then the collected phagocytes begin to squeeze between the endothelial cells of the
blood vessel to reach the damaged area. This migration, which resembles ameboid
movement, is called diapedesis; it can take as little as 2 minutes
6. The phagocytes then begin to destroy invading microorganisms by phagocytosis.
As mentioned earlier, certain chemicals attract neutrophils to the site of injury
(chemotaxis). These include chemicals produced by microorganisms and even other
neutrophils; other chemicals are kinins, leukotrienes, chemokines and components of
the complement system. Chemokines are cytokines that are chemotactic for
phagocytes and T cells and thus stimulate both the inflammatory response and an
adaptive immune response. The availability of a steady stream of neutrophils is
ensured by the production and release of additional granulocytes from red bone
marrow. As the inflammatory response continues, monocytes follow the granulocytes
into the infected area. Once the monocytes are contained in the tissue, they undergo
changes in the biological properties and become free macrophages. The granulocytes
predominate in the early stages of infection but tend to die off rapidly. Macrophages
enter the picture during a later stage of infection, once the granulocytes have
accomplished their function. They are several times more phagocytic than
granulocytes and are large enough to phagocytize tissue that has been destroyed,
granulocytes have been destroyed, and invading microorganisms.
After granulocytes or macrophages engulf large numbers of microorganisms and
damaged tissue, they themselves eventually die. As a result, pus forms, and its
formation usually continues until the infection subsides. At times, the pus pushes to
the surface of the body or into an internal cavity for dispersal. On other occasions the
pus remains even after the infection is terminated. In this case, the pus is gradually
destroyed over a period of days and is absorbed into the body.
As effective as phagocytosis is in contributing to innate resistance, there are times
when the mechanism becomes less functional in response to certain conditions. For
example, with age, there is a progressive decline in the efficiency of phagocytosis.
Recipients of a heart or kidney transplants have impaired innate defenses as a result of
deceiving drugs that prevent the rejection of the transplant. Radiation treatments can
also depress immune responses by damaging red bone marrow. Even certain disease
such as AIDS and cancer can cause defective functioning of innate defenses. Finally,
individuals with certain genetic disorders produce fewer or impaired phagocytes.

TISSUE REPAIR

The final stage of inflammation is tissue repair, the process by which tissues replace
dead or damaged cells. Repair begins during the active phase of inflammation, but it
cannot be completed until all harmful substances have been removed or neutralized at
the site of injury. The ability to regenerate or repair depends on the type of tissue. For
example, skin has a high capacity for regeneration, whereas cardiac muscle tissue has
a low capacity to regenerate.
A tissue is repaired when its stroma or parenchymal produces new cells. The
stroma is the supporting connective tissue and the parenchyma is the functioning part
of the tissue. For example, the capsule around the liver that encloses and protects it is
a part of the stroma because it is not involved in the functions of the liver are part of
the parenchyma. If only parenchymal cells are active in repair, a perfect or near-
perfect reconstruction of the tissue occurs. A familiar example of a perfect
reconstruction is a minor skin cut, in which parenchymal cells are more active in
repair. However, if repair cells of the stoma of the skin are more active, scar tissue is
formed. As noted earlier, some microbes have various mechanisms that enable them
to evade phagocytosis. Such microbes often induce a chronic inflammatory response,
which can result in significant damage to body tissues. The most significant feature of
chronic inflammation is the accumulation and activation of machrophages in the
infected area. Cytokines released by activated machrophages induce fibroblasts in the
tissue stroma to synthsize collagen fibers. These fibers aggregate to form scar tissue
through a process called fibrosis. Since scar tissue is not specialized to perform the
functions of the previously healthy tissue, fibrosis can interfere with the normal
function of the tissue.

ANTIMICROBIAL PEPTIDES

Antimicrobial peptides or AMP’s may be one of the most important components of

innate immunity. AMP’s are short peptides that consist of a chain of about 12-50
amino acids synthesized on ribosomes. They were first discovered in the skin of frogs,
the lymph of insects, and human neutrophils, to date, over 600 AMP;s have been
discovered in nearly all plants and animals.
AMP’s have a broad spectrum of antimicrobial activities including activity against
bacteria, viruses, fungi, and eukaryotic parasites. Synthesis of AMP’s is triggered by
protein and sugar molecules on the surface of microbes. Cells produce AMP’s when
chemicals in microbes attach to Toll-like receptors.

The modes of actions of AMP’s include inhibiting cell wall synthesis; forming
pores in the plasma membrane, resulting lysis, and destroying DNA and RNA.
Among the AMP’s produced by humans are dermcidin which are produced by sweat
glands; defensins and cathelicidins produced by neutrophils, macrophages, and
epithelium; and thrombocidin produced by platelets.

Scientist’s are overly interested in AMP’s foe a number of reasons. Besides their
broad spectrum of activity, AMP’s have shown synergy (working toogether) with
other antimicrobial agents, so that the effect of them working together is greater than
that of either working separately. AMPs are also very stable over a wide range of pH.
What is particularly significant is that microbes do not appear to develop resistance
even though the microbes are exposed to them for a long period of time.

In addition to the killing effect of the AMP’s they also participate in a number of
immune functions. For example, AMP’s can sequester the LPS shed from gram-
negative bacteria preventing endotoxic shock. AMP’s have been found to be
vigorously attract dendritic cells, which destroy microbes by phagocytosis and
initiate an adaptive immune response. AMP’s have also shown to recruit mast cells,
which increase blood vessel permeability and vasodilation. This brings about
inflammation, which destroys microbes, limits the extent of damage, and initiates
tissue repair.