Digestive System 1. Describe the role of the pancreas and ... · 2-Protein Digestion The first...
Transcript of Digestive System 1. Describe the role of the pancreas and ... · 2-Protein Digestion The first...
Digestive System
1. Describe the role of the pancreas and liver in maintaining blood sugar
levels. Answer: Insulin hormone produce by pancreas secretes when blood sugar concentration is high
and causes liver and muscles to take up and store excess glucose as Glycogen. Also promotes
synthesis of protein and fats. LOWERS BLOOD SUGAR LEVEL. Glucagon another pancreatic
hormone secretes when blood sugar concentration is low and causes liver and muscles to break
down glycogen to glucose. Also, stops protein and fat synthesis. RAISES BLOOD SUGAR
LEVEL. In addition, liver stores glucose as Glycogen after eating, and breaks down glycogen to
glucose between eating to maintain the glucose concentration of the blood.
2. Discuss the complete digestion and absorption of starch, proteins and
lipids. Answer;
1- Starch digestion and absorption:
The first stage of digestion of starch begins in mouth. Salivary amylase produced by the salivary
glands and secreted into the mouth and acts on starch to break it into many molecules of maltose.
Maltose is later broken down in the system to glucose. Pancreatic amylase also acts on starch to
convert it to maltose. This process occurs in the duodenum, but amylase is produced by the
pancreas. Maltase produced in the small intestine converts maltose to glucose. Therefore, in two
places starch break downs to maltose: in the mouth by salivary amylase and in the small intestine
by pancreatic amylase. Finally, maltose molecules break down to glucose by maltase in small
intestine. These molecules (glucose) are small enough to absorb directly into blood stream
through the capillaries network of microvilli in intestine; therefore, this stage is absorption
process of glucose molecule.
Physical digestion in mouth
Amylase
Starch + Water-----------> Maltose
-----------> Digestion
Maltase
Maltose + Water -----------> 2 Glucose
Glucose -----------> Absorption (Microvilli’s capillaries network in intestine)
2-Protein Digestion
The first stage of digestion of proteins begins in mouth (mechanical digestion). The chemical
digestion of proteins begins in the stomach where Proteases break down proteins to peptides. There
are two types of proteases: Pepsin which produced by the gastric glands of the stomach and trypsin
which produced by the pancreas. First of all, pepsin enzyme in stomach break downs some protein
molecules, and the remaining protein molecules break downs in small intestine by trypsin which
secreted by pancreas. In these processes, proteins break down to peptides. Peptidases which
produced by the small intestine break down peptides into amino acids. These molecules (Amino
Acids) are small enough to absorb directly into blood stream through the capillaries network of
microvilli in intestine; therefore, this stage is the absorption process of amino acids molecules.
3-Lipid Digestion
The first stage of digestion of lipids begins in the mouth (mechanical digestion). Bile produced by
the liver stored in the gall bladder breaks down fat in the duodenum into fat droplets (mechanical
digestion). The breaking down of fats to fat droplets by bile called emulsification. Lipase produced
by the pancreas breaks down fat droplets into glycerol and 3 fatty acids (chemical digestion). These
molecules (fatty acids and glycerol) are small enough to absorb directly into lacteal system in
intestinal microvillus. So fatty acids enter the lacteals which will go back into the bloodstream
later at the Subclavian veins.
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3. How is the structure of the small intestine suited to its function? Answer: The small intestine is specialized for absorption in that the small intestine is long
with convoluted wall (folded walls). The structure of the small intestine contains millions
of microscopic folds which act to increase the surface area. The walls of the small intestine
have villi (finger-like projections along the walls). The villi themselves have tiny microvilli
on columnar epithelial cells. Within each villus are blood vessels and small lymph vessel
called a lacteal which absorbs fluids and returns it to the veins. Absorption occurs across
the walls of each villus by active transport (uses energy). Glucose and Amino acids enter
the blood vessels and travel to the liver. Glycerol and fatty acids enter the lacteals, which
will go back into the bloodstream later at the Subclavian veins.
4. Name the structures food passes through all the way from the mouth to
the anus.
This picture depicts all organs which are related to the digestive system.
The second one shows the pathway of food from the mouth to the anus. It should be
mention that normally the foods do not pass through the appendix.
5. Describe 4 functions of the liver.
Answer:
1. Destroys old red blood cells and converts hemoglobin to a product in bile.
2. Produces Bile that is stored in the gall bladder before entering the Duodenum where it
emulsifies fat.
3. Store Glucose as Glycogen after eating, and breaks down glycogen to glucose between
eating to maintain the glucose concentration of the blood.
4. Produces Urea from the breakdown of amino acids (deamination)
5. Makes Blood Proteins from amino acids.
6. Detoxifies the blood by removing poisonous substances and metabolizing them (converting
them to harmless substances).
6. How is the structure of the stomach suited to its function?
Answer:
The stomach is an expanded section of the gastrointestinal tract between the esophagus and the
duodenum of the small intestine. Stomach is a J-shaped organ which stores and churns food. The
churning helps physically digest food, which creates more surface area and results in a mushy
liquid called acid chyme. The inside of the stomach is composed of three layers, from the innermost
layer to the outermost layer: mucosa, sub-mucosa, muscularis externa, and the serosa. The mucosa
is where stomach acid is produced and secreted into the stomach. The sub-mucosa is layer
composed of connective tissue that separates the mucosa from the muscularis externa. The
muscularis externa is composed of three layers of smooth muscle: inner oblique, middle circular,
and outer longitudinal. These are the muscles that are primarily responsible for mixing material
that has come into stomach with digestive enzymes and moving the material through the stomach.
The final layer is the serosa, which is a layer of connective tissue that attaches and is continuous
with the peritoneum, the lining of the abdominal cavity. The stomach has a muscular folded tissue
contains gastric glands which secret pepsin, HCl, and mucus. Pepsin is an enzyme which digests
proteins. HCl makes the stomach environment acidic, and mucus protects stomach tissue from
burn due to acidic property of HCl. The pyloric sphincter at the end of the stomach controls the
amount of chyme that leave stomach into the small intestine. The acidic environment of stomach
kills the bacteria. The chemical digestion of proteins beings here. Gastrin is a hormone produced
by the lower part of the stomach which enters the blood stream and later stimulate the upper part
of the stomach to stimulate gastric glands to produce Pepsinogen and HCl. HCl and pepsinogen
react with each other to produce Pepsin. Pepsin chemically digests proteins to peptides. HCL can
burn the gut lining so a mucous layer is produced to prevent this from happening. If a portion of
the gut is burned it is called an ulcer. Pyloric Sphincter - Band of muscle which closes off the
lower part of the stomach and only allows small amounts (~1 teaspoon) of chyme to enter the small
intestine.
As a result, muscular structure of stomach helps physical digestion of food, while secretory portion
of stomach in one hand helps in chemical digestion, and on the other hands regulated its secretion
by different mechanism. Also, mucosal secretion of stomach protects it from burn by HCL.
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Respiratory System
1. Explain why breathing happens.
Answer:
The sole reason of breathing is maintain the correct concentration of oxygen. Without oxygen we
will die. The Respiratory System supplied the body with oxygen for tis energy production.
Without Oxygen, the body shuts down in minutes. The Respiratory System works closely with
the Circulatory System. CO2 concentration and H+ concentration are the PRIMARY STIMULI
that cause us to breathe. When Carbon Dioxide and/or Hydrogen ion concentration gets too high,
the Breathing center in the Medulla Oblongata is stimulated.
1. A nerve impulse is sent from the Medulla Oblongata to the diaphragm and rib cage.
2. The diaphragm contracts and lowers; the rib muscles contract (intercostal muscles) and
raise the ribs. These actions increase the size of the chest cavity. Increased volume,
decreases pressure.
3. A partial vacuum is created in the lungs (air pressure in the lungs is reduced).
4. Air Rushes into the lungs from outside in order to rebalance the pressure. This is the
process of inspiration.
In addition to the Respiratory Center in the Medulla Oblongata, there are other receptors
that can respond to stimuli:
a. Carotid bodies - in the carotid artery
b. Aortic bodies - in the aorta
These respond to high concentration of Hydrogen Ions but can also respond to levels of
carbon dioxide in the blood.
2. How the upper respiratory track is kept free of debris?
Answer: Cleansed of debris. This is a two-part process:
a. The initial cleaning is by the nose hairs and mucous in the nasal Passageways.
b. The second is the process that occurs further along were the accumulation of debris can no
longer get out of through the nose. This is the role of the mucous lining and the cilia along the
trachea and the bronchi. Pretty well any material other than the gasses of the inhaled air will get
caught in the mucous. The cilia are in constant motion beating the debris-laden mucous upward
towards the pharynx. When this material is detected at the back of the mouth, it is swallowed (or
coughed up and spit out)
3. Describe exhalation Answer:
- Expiration - Expelling Carbon Dioxide
1. When the lungs are full, stretch receptors in the alveoli are stimulated
2. The Medulla Oblongata is notified and stops sending messages.
3. The diaphragm and rib muscles relax.
4. The chest cavity gets smaller. Decreasing volume, which increases the pressure in the
lungs. Air is forced out.
4. Describe inhalation
Answer:
- Inspiration - Bringing Oxygen into the lungs
CO2 concentration and H+ concentration are the PRIMARY STIMULI that cause us to
breathe. When Carbon Dioxide and/or Hydrogen ion concentration gets too high, the
Breathing center in the Medulla Oblongata is stimulated.
A nerve impulse is sent from the Medulla Oblongata to the diaphragm and rib cage.
The diaphragm contracts and lowers; the rib muscles contract (intercostal muscles) and
raise the ribs. These actions increase the size of the chest cavity. Increased volume,
decreases pressure.
A partial vacuum is created in the lungs (air pressure in the lungs is reduced).
Air Rushes into the lungs from outside in order to rebalance the pressure. This is the
process of inspiration.
5. How is the structure of the alveoli suited to their function? Answer:
Area where gas exchange occurs is alveoli. They are very numerous. Up to 300 million alveoli in
the human lung. This provides a great surface area for diffusion of gases. They are very thin-
walled (one cell) Alveolar walls are only one cell thick. This aids in diffusion. The alveoli have a
coating of lipoprotein on their inner surface. This helps to maintain surface tension thus
preventing them from collapsing and sticking together during exhalation. They are supplied with
stretch receptors. These are nerve endings that are sensitive to stretch. During inhalation, these
signal when the alveoli are full enough (stretched). This marks the onset of exhalation. The
alveoli surfaces have a very rich blood supply from the pulmonary capillaries to ensure
maximum diffusion. They are highly vascularized. Made up of Squamous (flat) Epithilial cells.
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Circulatory System
1. Describe the structure/function/produced where of the red blood cells,
white blood cells, platlets.
Answer:
1. Red Blood Cells - Erythrocytes
Live about 120 days.
Produced in Red Bone Marrow (In skull, ribs, vertebrae, and long bones.)
Myeloid stem cells form RBC. These stem cells are called Erythroblasts. Erythroblasts
will differentiate into Erythrocytes.
Produces about 5 million every second.
RBC contains a protein called Hemoglobin. Hemoglobin contains iron (gives blood its
red color). Picks up oxygen in the lungs (cooler blood). It combines with oxygen in the
lungs and releases it in the warmer tissues. Approximately 200,000,000 hemoglobin
molecules in one RBC. If hemoglobin was not packaged up in RBC, oxygen would leak
out of circulatory system.
RBC allow the blood to remain liquid so the heart does not have to work as hard.
Destroyed in the liver and spleen.
2. White Blood Cells - Leukocytes
Larger than RBC
They have nucleus (RBC do not)
less numerous than RBC (700:1)
Do not have a definite shape.
Function: Fights against infection
Phagocytic
Produce Antibodies
3. Platelets - (Thrombocytes)
Produce 2 billion a day.
Broken fragments of larger cells.
Very important role in blood clotting.
o Blood Clotting - Need three things in blood 1. Prothrombin
2. Fibrinogen
3. Platelets
Platelets clump at the site of the "leak" and partially close it.
The platelets and the injured tissue together release an enzyme called
THROMBOPLASTIN.
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2. Describe the structure/function – arteries, veins, capillaries
Answer:
Arteries:
Function: Largest are elastic (aorta & pulmonary). They stretch when the ventricles
eject the blood from the heart, then recoil, moving blood along. Large arteries
branch to form smaller arteries called arterioles. Transport blood away from the
heart.
Structure: Thick muscular, elastic walls.
Location: Usually found deep along bones
Veins:
Function: Transports blood back to the heart.
Structure: Thin walls; contain valves.
Location: Often on the surface surrounded by skeletal muscle.
Capillaries:
Function: Interconnect arteries to veins.
Structure: Very thin walls (1 cell thick).
Location: Everywhere; within a few cells of each other.
Capillaries have sphincter muscles that can dilate and constrict the vessel. If all
capillary beds were open at one time, it would decrease the blood pressure. If all the
capillary beds were closed, it would increase blood pressure.
3. Be able to name specific arteries and veins and their function
Aorta: This is the major blood vessel carrying oxygenated blood out of the heart. It leaves
the left ventricle, loops over top of the heart creating the structure known as the aortic arch
and descends along the inside of the backbone.
Function: Branches from this blood vessel feed the rest of the body.
Coronary Arteries and Veins:
The very first branches off the Aorta are the Coronary arteries. These relatively small
blood vessels can be seen on the surface of the heart.
Function: Feeds the heart muscle. (The heart does not receive its nutrients from the blood
that travels through it. The muscle is too dense and thick and the blood is traveling through
it too hard and fast.) Coronary Vein takes the "spent blood" back to the heart.
Carotid Arteries:
These branches
off the aortic
arch and take
the blood to the
head including
the brain.
Function: They
are highly
specialized in
that they
contain a
number of
different types
of nerve
endings:
Chemoreceptors that detect oxygen content, and Pressure Receptors that detect blood
pressure changes. These chemoreceptors help to maintain homeostasis.
Jugular Veins:
The match for the Carotid Artery. They do not contain valves. Blood flow is through
gravity.
Function: They conduct blood out of the head to the Superior Vena Cava.
Subclavian Arteries and Veins:
Also branch from the Aorta. Travels under the Clavicle.
Function: Branch to feed the arms (brachial artery). Veins collect blood from the arms.
Mesenteric Arteries:
These arteries branch off from the aorta as it travels posteriorly. They go to the intestines
where they branch into capillaries that can be identified as villi. For the purpose of this
course there is no corresponding mesenteric vein.
Function: Feeding the organs of the digestive system and picks up newly digested nutrients
in the body.
Hepatic Portal Vein:
Instead of a mesenteric vein, it is called a hepatic portal vein. Hepatic means liver; portal
indicates that there is a capillary bed on both ends of it.
Function: Brings blood from digestive tract to liver.
Hepatic Vein:
Once the liver has done its thing to the blood, the blood must return to the venous system.
Function: Carries blood from the liver to the posterior Vena Cava.
Renal Arteries and Veins:
The Renal Arteries branch off the dorsal aorta as it passes through the lumbar region of the
body.
Function: the arteries take blood to the kidneys while the renal veins take blood away
from the kidneys and back to the posterior Vena Cava.
Iliac Arteries and Veins:
When the dorsal aorta gets to the pelvic area. It branches into two Iliac Arteries, one goes
down each leg. Off the Iliac Arteries is another branch that feeds the upper leg. This is
called the Femoral Artery.
Function: To supply the legs with oxygenated blood and return deoxygenated blood to the
Posterior Vena Cava.
Anterior (Superior) and Posterior (Inferior) Vena Cava:
The largest vein of the body.
Function: Large vein that collects all the "spent" blood from smaller veins and carries it to
the heart (right atrium). The Anterior Vena Cava collects blood from the Upper body,
while the Posterior Vena Cava collects blood from the lower body.
Pulmonary Veins and Arteries:
The Pulmonary Circuit is comprised of the pulmonary trunk and arteries that deal strictly
with the heart and the lungs. It is the only artery in the body that carries deoxygenated
blood and the only vein in the body that carries oxygenated blood. (remember the function
of arteries is to carry blood away from the heart and the function of veins is to carry blood
to the heart)
Function: The arteries bring deoxygenated blood from the right side of the heart to the
lungs to get oxygen for the body, while the veins return oxygenated blood from the lungs
to the left atrium of the heart.
4. Explain the changes in blood pressure and velocity through the blood
vessels.
Answer Cross sectional area of the blood vessels (sum of the cross sectional area of all blood
vessels of one type) has a major effect on blood flow. As cross sectional area increases,
velocity of the blood decreases. Velocity of the blood decreases from aorta to arteries to
capillaries and increases in venules and veins. As CSA increases blood pressure
decreases. Once the blood pressure is lost in the capillaries it cannot be regained even
though CSA of venules and veins increases.
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5. Contrast pulmonary vs. Systemic circulation (include comparison of gas
content)
Answer:
Pulmonary Circuit:
Path that goes to and from the lungs.
From right ventricle through the pulmonary trunk--pulmonary arteries--lung capillaries--
pulmonary veins--left artium.
Carries carbon dioxide filled blood to lungs for cleaning.
Returns oxygen rich blood to heart.
Systemic Circuit:
Path from left ventricle to
body back to right atrium of heart.
Carries oxygen rich blood to
the body tissues.
Returns carbon dioxide filled
blood to the heart.
6. Describe 3 functions of haemoglobin. Answer:
Hemoglobin contains iron (gives blood its red color), and picks up oxygen in the lungs (cooler
blood). The main function of hemoglobin is to carry oxygen from the lungs to all the tissues of
the body. Also, some of carbon dioxide is transported from tissues to lungs through hemoglobin.
It combines with oxygen in the lungs and releases it in the warmer tissues. If hemoglobin was not
packaged up in RBC, oxygen would leak out of circulatory system.
In short, “(1) hemoglobin as molecular heat transducer through its oxygenation-deoxygenation
cycle, (2) hemoglobin as modulator of erythrocyte metabolism, (3) hemoglobin oxidation as an
onset of erythrocyte senescence, (4) hemoglobin and its implication in genetic resistance to
malaria, (5) enzymatic activities of hemoglobin and interactions with drugs, and (6) hemoglobin
as source of physiological active catabolites”( Giardina et al,1995 ).
7. Describe fetal circulation – special features/function
Answer:
Fetal systems have FOUR features not present in adult systems:
1. OVAL OPENING
Oval opening is an opening between the 2 atria; it is covered by a flap of tissue that acts like a
valve. Blood flows directly from the right atrium to the left atrium and allowing blood to bypass
the lungs, which do not work yet.
2. ARTERIAL DUCT
Arterial duct is a connection between the Pulmonary Artery and the Aorta. Blood flows from the
Pulmonary Artery to the Aorta, again allowing blood to bypassing the lungs.
3. UMBILICAL ARTERY AND VEIN
Umbilical Artery takes waste (Carbon Dioxide and Urea) to the Placenta from the fetus.
Umbilical Vein takes nutrients (Oxygen and Glucose and Amino Acids) to the Fetus from the
Placenta.
4. VENOUS DUCT
Venous duct is a connection between the Umbilical Vein and the Vena Cava. Blood coming from
the umbilical vein passes directly to the vena cava through the venous duct allowing blood to
bypass the liver.
8. Define systole vs. Diastole Answer:
Contraction of the heart is a two steps process. The term systolic pressure (or Systole) refers to
the pressure when the ventricles contract. This is the highest blood pressure reading.
The term diastolic pressure (diastole) refers to the blood pressure when the heart is at rest. This is
the lowest blood pressure reading.
9. Describe the tissue/fluid exchange Answer:
Blood is oxygenated as it passes through lung tissue. Oxygen (higher in concentration in the
inhaled air) diffuses through the thin walled tissues of the lung to capillaries and into the blood
where it bonds to hemoglobin (the iron containing protein that is part of the RBC). A single
hemoglobin molecule has four bonding sites for oxygen and is called oxyhemoglobin when
transporting oxygen.The blood reaches arterioles and then the capillaries where blood pressure
decreases. Nutrients (products of digestion) and oxygen diffuse into the tissues. The larger
particles in blood stay where they are because they are too big to get out. Because of these large
molecules, the blood is said to be hypertonic to the tissues. As a result, the water from the tissues
is drawn back into the venule side of the capillary bed. When the fluid returns it carries carbon
dioxide and wastes with it. Blood pressure on arteriole side of the capillary bed is higher than
osmotic pressure and will try and push substances such as oxygen, water, glucose and amino
acids out of blood into the tissues of the body.Blood pressure on the venule side of capillary is
lower than the osmotic pressure and therefore wastes such as Carbon Dioxide, ammonia and
water are forced from the tissues of the body into the blood.
10. Explain the hearts nervous control over heart rate.
Answer:
The rate of the heart can also be controlled by the nervous system.
The heart rate center is located in the Medulla Oblongata of the brain. The SA Node is
connected to the brain by the Vagus nerve (cranial nerve #10). This nerve pathway, part of
the Autonomic Nervous System (not under conscious control), has two system that affect the
Heart Rate:
1. Parasympathetic System - Causes the heart beat to slow down.
2. Sympathetic System - Causes the heart beat to increase during times of stress.
Factors such as need for oxygen or the blood pressure level determine which of these
systems become active. When the brain perceives that the blood is getting delivered to
the tissues too slowly, or if blood pressure is low, the brain will signal the SA Node to
speed up its contraction.
11. Describe the structure of the heart and function of the structures. Answer:
Left and Right Atria - Collecting Chambers
Right: Collects blood from Vena Cava.
Left: Collects blood from Pulmonary Veins.
Left and Right Ventricles - Pumps
Right: Sends blood to the lungs via the Pulmonary Trunk.
Left: Sends blood to the body via the Aorta
Atrioventricular Valves - Valves between the atria and ventricles.
Prevent backflow of blood
Right hand side ¨Tricuspids¨ - three cusps, or flaps
Left hands side ¨bicuspid¨ - two cusps
Chordae Tendineae - Strong, Fibrous strings that support the A.V. Valve.
Keeps the valves from inverting with the force of blood flow.
Semi-Lunar Valves - Between ventricles and arteries exiting heart.
Prevents back flow of blood from Pulmonary Trunk into right ventricle.
Prevents back flow of blood from aorta into left ventricle.
Pulmonary Trunk - Branches off to form the Pulmonary Arteries.
Receives blood from the right ventricle.
Septum - The wall of the Heart.
Separates the left and right sides of the Heart
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12. Be sure to be able to trace the flow of blood around the body eg. Head to
small intestine.
Answer:
Jugular vein to vena cava, vena cava to right atrium, right atrium to right ventricle, right
ventricle to pulmonary artery, pulmonary artery to the lung, lung to the pulmonary vein,
pulmonary vein to the left atrium, left atrium to the left ventricle, left ventricle to the aorta, aorta
( abdominal aorta)to the mesenteric artery. Oxygenated blood leaves the heart through the aorta,
which descends into the abdominal cavity as the abdominal aorta. The superior mesenteric artery
supplies the whole small intestine and extends branches up to the middle third of the transverse
colon.
13. Describe the lymphatic system structure/function. Answer:
Functions of the Lymphatic System:
1. Takes excess tissue fluid and sends it to the circulatory System. The Lymphatic System
joins the Circulatory System at the subclavian veins.
2. Products of fat digestion are absorbed into Lacteals, which lead to the Lymph Vessels
and Nodes.
3. Lymph Nodes produce Lymphocytes (a type of White Blood Cell).
4. Lymph Nodes act as filters and trap bacteria and other debris (helps to purify the body
fluids), attacks foreign substance (bacteria or viruses).
5. Lymphocytes produce antibodies. Each antibody fights a specific antigen (foreign
protein). Antigens are proteins found in the outer membrane of blood and it is the type of
protein found that determines the type of blood. Antibodies are proteins that attack
unwanted proteins which results in agglutination.
Antigen + Antibody --> Inactive complex.
Key Lymphatic Structures
Spleen:
Largest lump of Lymphatic Tissue.
Produces Lymphocytes and stores excess blood.
If your blood pressure is high, it stores blood so that blood pressure lowers.
If your blood pressure is low, it contracts and adds blood to the circulatory system, so that
blood pressure rises.
Thymus Gland:
Bi-lobed structure which is important in the maturing of some Lymphocytes.
Becomes smaller with age.
Tonsils and Appendix:
Also contain Lymphoid Tissue.
Thought to help remove invading organisms and viruses.
Lymphatic Tissue:
Produce lymphocytes and stores excess blood.
Structures in the Lymphatic System
Lymph Vessels:
Similar to veins, but fluids only travel in one direction. Contain lymph veins and
capillaries, but NO lymph arteries.
Lymph Nodes:
Small oval or round tissues which filter fluids and produce Lymphocytes.
Lacteals:
Blind sacs in villi of Digestive System which absorb products of Fat Digestion.
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Reference: Giardina, B., Messana, I., Scatena, R., & Castagnola, M. (1995). The multiple functions of hemoglobin. Crit Rev Biochem
Mol Biol, 30(3), 165-196. doi: 10.3109/10409239509085142