Introduction.
In mammals the respiratory organ is the lung which is situated on either side of the thoracic cavity flanking the heart4. In air breathing vertebrates the lung is either of the two primary respiratory organs into which the atmospheric air is entered when the pressure inside the thoracic cavity becomes negative. Once the exchange of gases took place, the rest of the air is forced out to the atmosphere by generating a positive pressure in side the thoracic cavity there by squeezing the lung tissues.
The principal function of the lung is to transport oxygen from the atmosphere into the bloodstream and to excrete carbon dioxide from the bloodstream into the atmospheric air4. This nature of exchange of oxygen and carbon dioxide is very essential for the existence of life. The oxygen taken in from the atmosphere into the bloodstream powers the production of chemical energy in the form of ATP via what is called an aerobic respiration and the carbon dioxide a by-product of the energy producing mechanism (metabolism) is removed from the system as carbon dioxide is toxic to cells and tissues at high concentrations.
Even though the main functions of the lungs are respiratory functions, it also plays several important non-respiratory functions as well. Some of these non-respiratory functions include, serving as a physical layer of soft, shock-absorbent protecting function to the heart; removing fat from the bloodstream and storing it, storing and metabolizing of glycogen and also filtering out small blood clots formed in the venous system of the body etc.

Overall, the lung reflects not only the principles of give and receive (the movement of gases between the organism and the environment), but also the interconnectedness of the parts of the body4. The lung provides a function directed toward the preservation and development of the entire body; in turn, the body as a whole, and its parts, provides for the betterment of the lung, including supplying nutrients, removal of wastes from the cells, and so forth.
The evolution of lungs played a crucial role in the development of complex organisms. In single-celled organisms including bacteria etc, exchange of gases from the environment it lives take place entirely by the process of simple diffusion. However in larger organisms, only a small proportion of cells are close enough to the surface for oxygen from the atmospheric air to enter into the organism – through diffusion. Thus, two major adaptations are seen in such organisms to attain great multicellularity. One such adaptation is to have an efficient circulatory system that conveys gases to and from the deepest tissues in the body, The second type of adaptation is to have a large, internalized respiratory system that centralizes the task of obtaining oxygen from the atmosphere and bringing it into the body, where it could rapidly be distributed to any part of the circulatory system.

Overview.
Most lungs have a complex, honeycomb like structure in appearance designed to maximize the surface area for exchange of gases. In addition, lungs are spongy and also moist, which prevents them from drying out. This feature of the lung (sponginess and the moisture) also makes the environment hospitable to the bacteria associated with many respiratory illnesses4.
Though certain basic features are similar and shared, the respiratory mechanisms and the anatomy of the lungs are adapted to the particular needs of the organism. Air enters through the trachea, (a cartilaginous tube like structure commonly referred to as the windpipe,) and subdivides into smaller airways called bronchi. In most air-breathing vertebrates, the bronchi further subdivide into finer pathways of branching airways, until they culminate in specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli, where exchange of gas take place.

Picture -2. Lungs dissected to show the Bronchial tree

Air enters and leaves the lungs via a conduit of cartilaginous passageways called the bronchi and bronchioles. In the image above, lung tissue has been dissected away to reveal the bronchioles.
Although the details of respiration differ depending on organism some of the basic mechanisms seem shared:
• The atmospheric air is brought into the animal via the airways; this pathway often consists of the nose, pharynx, larynx, trachea, and bronchi.
• The drawing and expulsion of air (called ventilation) is driven by muscular action which involved muscular tissues of the thorax and some abdominal muscles.
• The volume of the thoracic cavity is increased by relaxing the chest muscle and the Diaphragm (there by creating a negative pressure in the thoracic cavity) and vice – versa by muscular contractions.
Anatomy
The lungs of mammals have a spongy texture and are honeycombed with epithelium (a thin layer of tightly packed cells), a structure that maximizes the surface area for gas exchange.

A schematic depicting the bronchi, bronchial tree, and lungs.
Mammalian lungs are located in two cavities on either side of the heart. Though similar in appearance, the two lungs are not identical to each other.. Both are separated into lobes, with three lobes on the right and two on the left. The lobes are further divided into lobules, hexagonal divisions that are the smallest subdivision visible to the naked eye.
Two main bronchi (produced by the bifurcation of the trachea) enter the roots of the lungs. The bronchi continue to divide within the lung, and after multiple divisions, give rise to bronchioles. The bronchial tree continues branching until it reaches the level of terminal bronchioles, which lead to alveolar sacs. The latter are made up of clusters of alveoli, which resemble individual grapes within a bunch. Each alveolus is tightly wrapped in blood vessels, and it is here that gas exchange occurs. Deoxygenated blood from the heart is pumped through the pulmonary artery to the lungs, where oxygen diffuses into blood and is exchanged for carbon dioxide in the hemoglobin of the erythrocytes. The oxygen-rich blood returns to the heart via the pulmonary veins to be pumped back into systemic circulation.
Mechanism of respiration

The human respiratory system9.
The muscular diaphragm situated at the bottom of the thorax largely drives breathing. The contraction of the diaphragm pulls down the bottom of the cavity in which the lung is enclosed. This increases the volume and creates a negative pressure causing the air enters through the oral and nasal cavities; it flows through the larynx and into the trachea, which branches out into bronchi. Relaxation of the diaphragm has the opposite effect, passively recoiling during normal breathing. During exercise, the diaphragm contracts, forcing the air out more quickly and forcefully. The rib cage also is able to expand and contract to some degree, through the action of other respiratory and accessory respiratory muscles. As a result, air is sucked into or expelled out of the lungs, always moving down its pressure gradient. This type of lung is known as a bellows lung as it resembles a blacksmith’s bellows. Because mammalian lungs culminate in dead ends (the alveolar sacs), the pathway of airflow is tidal (i.e., air comes in and flows out by the same route).
Non-respiratory functions.
In addition to respiratory functions such as gas exchange and regulation of hydrogen ion concentration, the lungs also play important non-respiratory roles, which help to ensure proper biological function.
Followings are some of the non-respiratory functions of the respiratory system;
1) Lung Defense mechanisms.
2) Vocalization
3) Coughing and sneezing
4) Alter the pH of blood by facilitating alterations in the partial pressure of carbon dioxide.
5) Filter out small blood clots formed in veins.
6) Filter out gas micro-bubbles occurring in the venous blood stream such as those created after scuba diving during decompression3, 6, and 7.
7) Influence the concentration of some biological substances and drugs used in medicine in blood
Metabolic function
9) Endocrine function
10) May serve as a layer of soft, shock-absorbent protection for the heart, which the lungs flank and nearly enclose.
11) Temperature control function.
12) Lung Defense Mechanisms:
The respiratory passages that lead from the exterior to the alveoli do more than serve as gas conduits. They prevent entrance of the harmful substances in to the body by several mechanisms.
1. Physical and physiological mechanisms.
2. Humoral and cellular mechanisms.
Physical and physiological mechanisms.
They humidify and cool or warm the inspired air and maintain the integrity of the mucosa7.
1. Humidification;
 This action prevents dehydration.
2. Prevention of Particles entering the Respiratory tract
3. This is an adaptation of the respiratory system to prevent particles from out side in to the Respiratory tract.
 The particles more than 10 micro meters in diameter are removed in the nostrils or nasopharynx.
 Particles more than 20micro meter in diameter are deposited in the nose or conjunctivae.
 5 to 10 micro meter size particles are impacted in the carina.
 1 to 2 micro meter size particles are deposited in the distal lungs.
4. Expulsion of Particles; this is another defense mechanism of the respiratory system.
 By coughing,
 Sneezing and gagging.

5. Respiratory tract secretions;
 Mucus
 Gelatinous substance consisting chiefly of acid and neutral polysaccharides.
 Consists of a 5 micro meter thick gel that is relatively impermeable to water.
 The gel layer is secreted by the Goblet cells and mucus glands. Under normal conditions the tips of the cilia are in contact with the under surface of the gel phase and coordinate their movements to push the mucus blanket upwards. One of the major complications of cigarette smoking is the reduction of the mucociliary action which leads to recurrent infections.
The epithelium of the Para nasal sinuses produce nitrous oxide which is bacteriostatic and prevent infections.
Humoral and cellular mechanisms.
It is observed that the bronchial secretions also contain secretary immunoglobulin (IgA) and other substances that help to resist infections6.
Non specific soluble factors.
 The lung secretions contain Alpha – 1 antitrypsin – This has an inhibitory action on chemical substances such as Chymotrypsin, Trypsin. It also neutralizes the proteases and elastases6.
 Lysozyme – formed in the granulocytes. They are having strong bactericidal properties6.
 Lactoferin – Synthesized from the epithelial cells and neutrophil granulocytes. They also fight against bacteria using their bactericidal properties6.
 Interferon – produced in response to a viral infection. It is a potent suppressor of the lymphocyte functions and lowers the threshold for mast cell histamine release. At the same time it renders the other cells resistant to infection by any other virus6, 7.
 Complements – Present in the secretions in association with antibodies. It plays an important cytotoxic role.

Pulmonary Alveolar Macrophages.
These are produced by the bone marrow and migrate to the lungs via the blood stream. They phagocytose particles including bacteria and are removed by the mucociliary escalator, lymphatic and blood stream. They are the dominant cells in the airway.

Lymphoid Tissue.
The Bronchus – Associated Tissue (BALT) consists of lymphocytes present either in aggregates (Tonsils and adenoids.) or scattered. This is an important immunological defense mechanism. The Lymphocytes once sensitized to antigen produce secretory IgA, IgG and IgE.

Vocalization.
The mechanism of speech in human beings is a result of the movement of gas through the larynx, pharynx and mouth. This produces sound that allows humans to speak, or phonate. In birds vocalization, or singing, occurs via the syrinx, an organ located at the base of the trachea. The vibration of air flowing across the larynx (vocal chords), in humans, and the syrinx, in birds, results in sound. Because of this, movement of gas is extremely important and vital for the purpose of communication.
Coughing and sneezing.
By the Irritation of nerves present within the nasal passages or airways, phenomenon of Coughing and sneezing can be induced. This is a protective mechanism. During the action of coughing or sneezing as a response to some irritation of nerves in the nasal passages the air is expelled forcefully out from the trachea or nose, respectively. In this manner, irritants caught in the mucus which lines the respiratory tract are expelled or moved to the mouth where they can be swallowed. This mechanism plays an important role to ensure a stable and safe response to the fluctuations in the outside environmental changes and weather conditions.
Acid-base homeostasis.
The body is capable of regulating its inner environment physiologically via the acid-base homeostasis as a part of the body’s ability to ensure its stability in response to fluctuations in the outside environment and the weather. Human homeostasis concerning the proper balance between acids and bases, in other words the pH. The body is very sensitive to its pH level. Outside the range of pH that is compatible with life, proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself.
The body compensates the acid-base imbalance which occurs in the body by regulating the rate of ventilation. By changing the ventilation rate, the body can alter the concentration of carbon dioxide in the blood, which alters the pH.
Respiratory Regulation of Acid-Base Balance.
How is the Respiratory System Linked to Acid-base Changes?
‘Respiratory regulation’ refers to changes in pH due to pCO2 changes from alterations in ventilation. This change in ventilation can occur rapidly with significant effects on pH. Carbon dioxide is lipid soluble and crosses cell membranes rapidly, so changes in pCO2 result in rapid changes in [H+] in all body fluid compartments1.
A quantitative appreciation of respiratory regulation requires knowledge of two relationships which provide the connection between alveolar ventilation and pH via pCO2. These 2 relationships are:
• First equation – relates alveolar ventilation (VA) and pCO2
• Second equation – relates pCO2 and pH.
The two key equations are outlined in the boxes below:
First Equation: Alveolar ventilation – Arterial pCO2 Relationship
Relationship: Changes in alveolar ventilation are inversely related to changes in arterial pCO2 (& directly proportional to total body CO2 production).
paCO2 is proportional to [VCO2 / VA]
where:
• paCO2 = Arterial partial pressure of CO2
• VCO2 = Carbon dioxide production by the body
• VA = Alveolar ventilation
Alternatively, this formula can be expressed as:
paCO2 = 0.863 x [ VCO2 / VA ]
(If VCO2 has units of mls/min at STP and VA has units of l/min at 37C and
atmospheric pressure.)
Second Equation: Henderson-Hasselbalch Equation
Relationship: These changes in arterial pCO2 cause changes in pH (as defined in the Henderson-Hasselbalch equation):
pH = pKa + log { [HCO3] / (0.03 x pCO2) }
or more simply: The Henderson equation:
[H+] = 24 x ( pCO2 / [HCO3] )
The key point is that these 2 equations can be used to calculate the effect on pH of a given change in ventilation provided of course the other variables in the equations (e.g. body’s CO2 production) are known.
The next question to consider is how all this is put together and controlled, that is, how does it works?
Control System for Respiratory Regulation
Using the model of a simple servo control system the control system for respiratory regulation of acid-base balance can be considered. The components of such a simple model are a controlled variable and a central integrator. That interprets the information from the sensor and an effector mechanism which can alter the controlled variable. The servo control means that the system works in such a way as to attempt to keep the controlled variable constant or at a particular set-point. This means that a negative feedback system is in operation and the elements of the system are connected in a loop.
Control systems in the body are generally much more complex than this simple model but it is still a very useful exercise to at first attempt such an analysis.

Control System for Respiratory Regulation of Acid-base Balance
Control Element Physiological or Anatomical Correlate Comment
Controlled variable Arterial pCO2 A change in arterial pCO2 alters arterial pH (as calculated by use of the Henderson-Hasselbalch Equation).
Sensors Central and peripheral chemoreceptors Both respond to changes in arterial pCO2 (as well as some other factors)
Central integrator The respiratory center in the medulla
Effectors The respiratory muscles An increase in minute ventilation increases alveolar ventilation and thus decreases arterial pCO2 (the controlled variable) as calculated from ‘Equation 1′(discussed previously). The net result is of negative feedback which tends to restore the pCO2 to the ‘set point’.
Filter out small blood clots formed in veins.
Lower extremity deep vein thrombosis (DVT) most often results from impaired venous return (e.g., in immobilized patients), endothelial injury or dysfunction (e.g., after leg fractures), or hypercoagulability7, 8, 10.
Upper extremity DVT most often results from endothelial injury due to central venous catheters, pacemakers, or injection drug use. Upper extremity DVT occasionally occurs as part of superior vena cava (SVC) syndrome or results from a hypercoagulable state or subclavian vein compression at the thoracic outlet. The compression may be due to a normal or an accessory first rib or fibrous band (thoracic outlet syndrome) or occur during strenuous arm activity (effort thrombosis, or Paget Schroetter syndrome, which accounts for 1 to 4% of upper extremity DVT cases).
DVT usually begins in venous valve cusps. Thrombi consist of thrombin, fibrin, and RBCs with relatively few platelets (red thrombi); without treatment, thrombi may propagate proximally or travel to the lungs and may cause pulmonary embolism which may be fatal. The Lungs contain a fibrinolytic system that lyses clots in the pulmonary vessels.
Decompression sickness.
Inert gases are dissolved in body tissues and liquids while the body is under pressure, say during a scuba dive at depth. On ascent from the dive, the excess inert gas comes out of solution in a process called “outgassing” or “offgassing”. Normally most offgassing occurs by gas exchange at the lungs during exhalation3, 6. If inert gas is forced to come out of solution too quickly to allow outgassing at the lungs then bubbles may form in the blood stream or within solid tissues inside the body. This causes the signs and symptoms of DCS which includes itching skin, rashes, joint pain and neurological disturbance. The formation of bubbles in the skin or joints results in the milder symptoms, while large numbers of bubbles in the venous blood can cause pulmonary (lung) damage. The most severe types of DCS interrupt—and ultimately damage—spinal cord nerve function, which may lead to paralysis, sensory system failure, and death.
In the presence of a right-to-left shunt, such as a patent foramen ovale (PFO), venous bubbles may migrate to the arterial system, resulting in an arterial gas embolism which may damage the brain.

Metabolic and Endocrine Functions.
The lungs have a number of metabolic functions.
They manufacture of surfactants for their use. They release a number of substances that enter the systemic arterial blood flow. They also remove a number of substances from the circulation that reaches via the pulmonary blood flow. Prostaglandins are removed from the circulation, but they are also synthesized in the lungs and release to the circulation when the lung tissues are stretched7.
The Lung also activate one hormone; the physiologically inactivate deca peptide angiotensin – 1 is converted to the pressor, aldosterone stimulating angiotensin – 11 in the pulmonary circulation. A Large amount of the angiotensin-converting enzyme responsible for this conversion is located on the endothelial cells of the pulmonary capillaries. The converting enzyme also inactivates bradykinin.
Removal of serotonin and norepinephrine reduces the amount of these vasoactive substances reaching the systemic circulation.

Biologically active substances metabolized by the Lungs.
Synthesized and used in the lungs.
• Surfactant.
Synthesized and stored and released into the blood.
• Prostaglandins.
• Histamine.
• Kallikrein.

Partially removed from the blood.
• Prostaglandins.
• Bradykinin.
• Adenine nucleotide.
• Serotonin.
• Norephrine.
• Acetylcholine.

Activated in the Lungs.
Angiotensin 1 → Angiotensin 113, 6, 7.

Temperature control.
Panting in dogs and some other animals provides a means of controlling body temperature. This physiological response is used as a cooling mechanism7.