Respiratory tract antimicrobial defense system
Encyclopedia
The respiratory tract antimicrobial defense system is a layered defense mechanism which relies on components of both the innate
and adaptive immune system
s to protect the lungs and the rest of the respiratory tract
against inhaled microorganism
s.
In the first line of defense, inhaled bacteria are trapped by mucus
and are swept toward the pharynx
and are swallowed. Bacteria which penetrate the mucous layer are dealt with a second line of defense which includes antimicrobial peptides that are secreted by the surface epithelium
of the respiratory tract which kill many strains of bacteria. Those bacteria that are resistant to antimicrobial peptides are killed by a variety of reactive oxygen species
produced by phagocyte
s. In a third line of defense and as a last resort, persistent bacterial infections which escape the innate immune system are eliminated by the adaptive immune system.
and kaliocin-1 both with antimicrobial activity.
-producing NADPH oxidase
enzyme complex. Other cells in the respiratory tract also produce superoxide and hydrogen peroxide through the activity of dual oxidase 2 proteins, also known as Duox2.
The superoxide generated by these enzymes complexes dismutate
s into hydrogen peroxide
which in turn is used by myeloperoxidase
to produce bactericidal hypochlorous acid
. In addition, the submucosal glands
of the respiratory tract secrete myeloperoxidase and lactoperoxidase
(LPO) that catalyzes the oxidation of thiocyanate
and detoxify hydrogen peroxide or ROS to the antimicrobial hypothiocyanite
.
The oxygenated compounds produced by the lactoperoxidase system does not attack DNA and is not mutagenic and is known to be safe. Hypothiocyanite generated through this pathway displays broad spectrum bactericidal activity including potent antibacterial action on H. pylori
.
patients is decreased resulting in a reduced production of the antimicrobial hypothiocyanite and consequently contributes to the increased risk of airway infection.
status by the EMEA
and the FDA.
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
and adaptive immune system
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
s to protect the lungs and the rest of the respiratory tract
Respiratory tract
In humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...
against inhaled microorganism
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...
s.
In the first line of defense, inhaled bacteria are trapped by mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
and are swept toward the pharynx
Pharynx
The human pharynx is the part of the throat situated immediately posterior to the mouth and nasal cavity, and anterior to the esophagus and larynx. The human pharynx is conventionally divided into three sections: the nasopharynx , the oropharynx , and the laryngopharynx...
and are swallowed. Bacteria which penetrate the mucous layer are dealt with a second line of defense which includes antimicrobial peptides that are secreted by the surface epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
of the respiratory tract which kill many strains of bacteria. Those bacteria that are resistant to antimicrobial peptides are killed by a variety of reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
produced by phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...
s. In a third line of defense and as a last resort, persistent bacterial infections which escape the innate immune system are eliminated by the adaptive immune system.
Lactoferrin
Lactoferrin (LF) is a multifunctional protein which is an essential part of the respiratory tract antimicrobial defense system. LF proteolysis produces the small peptides lactoferricinLactoferricin
Lactoferricin is an amphipathic, cationic peptide with anti-microbial and anti-cancer properties. It can be generated by the pepsin-mediated digestion of lactoferrin....
and kaliocin-1 both with antimicrobial activity.
Reactive oxygen species, oxygenated compounds
Phagocytes possess a superoxideSuperoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
-producing NADPH oxidase
NADPH oxidase
The NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma membrane as well as in the membrane of phagosome.-Subunits:It is made up of six subunits...
enzyme complex. Other cells in the respiratory tract also produce superoxide and hydrogen peroxide through the activity of dual oxidase 2 proteins, also known as Duox2.
The superoxide generated by these enzymes complexes dismutate
Disproportionation
Disproportionation, also known as dismutation is used to describe a specific type of redox reaction in which a species is simultaneously reduced and oxidized so as to form two different products....
s into hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
which in turn is used by myeloperoxidase
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...
to produce bactericidal hypochlorous acid
Hypochlorous acid
Hypochlorous acid is a weak acid with the chemical formula HClO. It forms when chlorine dissolves in water. It cannot be isolated in pure form due to rapid equilibration with its precursor...
. In addition, the submucosal glands
Submucosal glands
Submucosal glands can refer to:*Esophageal glands, the submucosal glands of the esophagus.*Brunner's glands, the submucosal glands of the duodenum.*Submucosal glands in the upper airways of mammals....
of the respiratory tract secrete myeloperoxidase and lactoperoxidase
Lactoperoxidase
Lactoperoxidase is a peroxidase enzyme secreted from mammary, salivary, and other mucosal glands that functions as a natural antibacterial agent. Lactoperoxidase is a member of the heme peroxidase family of enzymes. In humans, lactoperoxidase is encoded by the LPO gene.Lactoperoxidase catalyzes...
(LPO) that catalyzes the oxidation of thiocyanate
Thiocyanate
Thiocyanate is the anion [SCN]−. It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Organic compounds containing the functional group SCN are also called thiocyanates...
and detoxify hydrogen peroxide or ROS to the antimicrobial hypothiocyanite
Hypothiocyanite
Hypothiocyanite is the anion [OSCN]- and the conjugate base of hypothiocyanous acid. It is an organic compound part of the thiocyanates as it contains the functional group SCN. It is formed when an oxygen is singly bonded to the thiocyanate group...
.
The oxygenated compounds produced by the lactoperoxidase system does not attack DNA and is not mutagenic and is known to be safe. Hypothiocyanite generated through this pathway displays broad spectrum bactericidal activity including potent antibacterial action on H. pylori
Helicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
.
Cystic fibrosis
bethcrespThiocyanate secretion in cystic fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
patients is decreased resulting in a reduced production of the antimicrobial hypothiocyanite and consequently contributes to the increased risk of airway infection.
Therapeutic applications
Lactoferrin with hypothiocyanite for the treatment of cystic fibrosis has been granted orphan drugOrphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status by the EMEA
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
and the FDA.