Lecture 2: Injury, Inflamation, and Repair

general pathology

A basic reactions or processes common to most tissues

specific pathology

A specific response or process in specific organs or tissues

etiology

cause of disease

pathogenesis

the manner in which a disease develops

hypoxia

decreased oxygen supply

anoxia

absence of oxygen due to the availability

asphyxia

absence of oxygen due to interruption of breathing (suffocation)

ischemia

decreased blood flow (loss of oxygen and nutrients)

What are six acquired causes of cell injury?

1)hypoxia/ischemia

2)physical damage

3)chemical damage

4)immunological

5)nutritional deficiency

6)infection

What are two intrinsic causes of cell injury?

1)genetic derangements (mutations)

2)normal aging process

What are four factors that are common in mechanisms of cell injury?

1)calcium (increased intracellular)

2)ATP (reduction)

3)membrane permeability

4)oxygen (reactive species present or decreased amount)

How does increased intracellular calcium promote cell injury?

Increased intracellular calcium activates phospholipase and protease, which break down cell membranes. It also activates endonucleases, which cause damage to nuclear/chromatin structures.

How do reactive oxygen species (ROS) promote cell injury?

Increased ROS leads to lipid peroxidation of membranes (breakdown), oxidative modification of proteins, and DNA damage.

reversible cell injury

impairs cell function but does not result in cell death

Ex/cellular swelling or fatty change

irreversible cell injury

autolysis and apoptosis

Ex/denaturation of proteins or membrane lipids

What are the five types of necrosis?

1)coagulative necrosis

2)liquefactive necrosis

3)caseous necrosis (special)

4)enzymatic fat necrosis (special)

5)gangrenous necrosis (special)

necrosis

irreversible cell death that is passive (does not require energy)

coagulative necrosis

A loss of nucleus, but cell shape and organ structures are preserved by the coagulation of proteins.

Ex/myocardial infarction

liquefactive necrosis

Influx of neutrophils releases catalytic enzymes that destroy cell outlines and tissue structure.

Ex/bacterial abscess (puss)

caseous necrosis

It has a cheese-like appearance and is typically seen in tuberculosis infections. It results from a combination of coagulative and liquefactive necrosis, forming granulomas with central necrotic debris.

enzymatic fat necrosis

Enzymatic fat necrosis occurs when pancreatic enzymes digest fat tissue, often seen in acute pancreatitis.

gangrenous necrosis

Gangrenous necrosis is tissue death due to loss of blood supply, commonly affecting limbs. It can be dry (coagulative), wet (with bacterial infection and liquefaction), or gas gangrene (caused by Clostridium species).

infarction

Process of coagulative necrosis that occurs distal to an occlusion in an artery feeding the tissue

apoptosis

programmed cell death that requires energy

What is the difference between apoptosis and necrosis?

Apoptosis is a controlled, energy-dependent process of programmed cell death that avoids inflammation and helps maintain tissue health.

Necrosis is an uncontrolled, often injury-induced cell death that leads to cell rupture and triggers inflammation in surrounding tissues.

How is apoptosis induced?

1)withdrawal of tropic factors (hormones or growth factors)

2)engagement of death receptors

Compare necrosis and apoptosis:

necrosis: non-physiological, unregulated, no energy required, cell membrane leakage, death of cell groups, and inflammatory response

apoptosis: physiologic and non-physiologic, highly regulated, energy dependent, cell membrane intact, death of an individual group of cells, and no inflammatory response

hyperplasia

increase in number of cells

hypertrophy

increase in cell size

metaplasia

premalignant condition where a cell type is replaced with a different cell type

Ex/barrett's metaplasia of the esophagus

premalignant

A lesion or process that will probably transform into cancer

amyloidosis

the accumulation of the abnormal protein amyloid in the kidneys and other organs that can lead to organ damage, as well as renal failure

hemachromatosis

An inherited disorder with an abnormal excess of iron leads to deposition in other parts of the body

monocyte

a phagocytic WBC found in the blood

neutrophil

A type of white blood cell that engulfs invading microbes and contributes to the nonspecific defenses of the body against disease.

lymphocyte

A type of white blood cell that make antibodies to fight off infections

inflamation

localized response to infection that is designed to protect the host, but excessiveness can be damaging to the host

What WBCs are found in acute inflammation?

neutrophils

What WBC are found in chronic inflammation?

lymphocytes and monocytes

Describe acute inflammation

-infiltration of tissue w/neutrophils

-rapid onset (minute to hour) and transient

-phagocytosis of bacteria and necrotic tissue

-innate immune response

Describe chronic inflammation

-infiltration of tissue w/monocytes and lymphocytes

-slow persistent onset (24 hours)

-phagocytosis, secrete cytokines, kill infected cells, and reject foreign tissue

-adaptive immune response

What is the sequence of events for acute inflammation?

1)increased blood flow to the region (vasodilation)

2)deposition of fluid and plasma proteins

3)accumulation of neutrophils from the microcirculation

4)endothelial damage causes more edema

edema nasal polyp

swelling (edema) within the nasal sinus that is common with asthma, allergies, or chronic sinusitis

histamine

A chemical secreted by mast cells that causes vasodilation of arterioles and increased permeability of venules. This response causes a fluid leak and is a common allergic response.

serotonin

A chemical in platelets that has a similar activity to histamine

inflammatory complement system

A series of plasma proteins with proteolytic activity that, when contacted with bacteria or antibody-bound bacteria/antigen, initiates a cascade of activated components.

What is the function of C3a and C5a?

vasodilation and permeability

What is the function of C3b and C3bi?

act as an opsonin (attach to bacterial cell wall and promote phagocytosis by neutrophils)

What is the function of C5a?

chemotactic (attractor) agent for neutrophils

What are two arachidonic acid metabolites that affect acute inflammation?

1)prostaglandins (inhibited by aspirin)

2)leukotrienes (allergic response)

All leukocyte traffic requires adhesion between surface of __________ _________ _______ and _________ _______ _______

apposing extracellular cells and extracellular matrix proteins

How do leukocytes transmigrate between endothelial cells and cross the basement membrane?

They are initially tethered to endothelial cells, which causes them to slowly roll until they firmly adhere and cross the basement membrane

What are the three types of cell adherence molecules?

1)selectins

2)ICAMs

3)integrins

integrins

Transmembrane heterodimers (alpha-beta) that are important for cell-cell and cell-membrane interactions. They are expressed on all leukocytes.

Ex/Mac-1 (neutrophil) and LFA-1 (lymphocyte)

ICAM-1

Expressed at low levels on endothelial cells that become super-induced in the presence of cytokines, which are released by lymphocytes and macrophages. They bind to LFA-1 and Mac-1

L-selectin

Expressed on monocytes, neutrophils, and lymphocytes to mediate adhesion to carbohydrate ligands induced on endothelial cells that are inflamed.

How does expression of integrins increase?

activation of leukocytes (ICAM-1 on endothelial cell)

-neutrophils (MAC-1) within minutes

-lymphocytes (LFA-1) couple days

How does the affinity of integrins increase?

chemokines (change conformation to increase affinity)

selectin-mediated adhesion

rapid-rate, low binding affinity, too weak to stop cells, and loose rolling interaction

integrin-mediated adhesion

slow-rate, high bonding affinity, and firm adherence

What is responsible for loose rolling interaction?

selectins

What is responsible for firm adherence?

integrins

What are three outcomes after inflammation?

1)complete resolution (regain function)

2)tissue replacement (fibrosis)

3)chronic inflammation (persistent damage)

angiogensis

formation of new blood vessels

fibrogenesis

migration and proliferation of fibroblasts that cause the development of fibrous tissue

granulation tissue

new tissue that is pink/red in color and composed of fibroblasts and small blood vessels that fill an open wound when it starts to heal

What is the major regulatory molecule for angiogenesis?

vascular endothelial growth factor (VEGF)

What is the major regulatory molecule for fibrogenesis?

transforming growth factor-beta (TGF-beta)

In ACUTE inflammation, which of the following often causes damage to the tissue?

A. Toxic enzymes secreted by infiltrating T lymphocytes

B. Hydrolytic enzymes and reactive oxygen species released from neutrophils

C. Overactive and persistent monocyte phagocytosis

D. Caspase activation in tissue-resident macrophages

E. The secretion of endonucleases by infiltrating neutrophils, which breaks down cells' DNA5

B. Hydrolytic enzymes and reactive oxygen species released from neutrophils

Damage to epithelial cells lining the alveoli (microscopic air

sacs in the lung) by bacteria often results in which of the following?

A. Complete resolution, with return of normal function.

B. Scar formation, with thickening of alveolar walls by collagen.

C. Pulmonary edema.

D. Decreased gas exchange.

E. All of the above are correct.

E. All of the above are correct.

The cellular events that occur in apoptosis include which of the following?

A. The secretion of Ca+2 ions from the cell

B. Suppression of integrin expression

C. Hyperoxidation of plasma membrane lipids

D. Rapid decrease in cell's energy stores

E. Release of cytochrome C from mitochondria into the cytosol

A. The secretion of Ca+2 ions from the cell

What key feature of L-selectin renders it so uniquely effective in its particular role in leukocyte-endothelial adhesion?

A. Their expression on the surface of all leukocytes

B. They adhere especially tightly (high affinity) to ligand on endothelium

C. It does not have to be induced by cytokines

D. It is a target for inside-out signaling

E. It binds to its ligand with a very high on-rate

E. It binds to its ligand with a very high on-rate

In tissue repair, fibroblast proliferation and collagen

secretion is stimulated by which one of the following?

A. complement component C5a

B. transforming growth factor-beta (TGF-beta)

C. interferon

D. tumor necrosis factor alpha (TNF-alpha)

E. macrophage chemokines

B. transforming growth factor-beta (TGF-beta)

Stimuli that initiate an inflammatory response must induce the

secretion of a cytokine such as IL-1 or gamma-interferon for which

one of the following reasons:

A. To diffuse toward blood vessels and cause their increased permeability

B. To activate macrophages to become more phagocytic

C. To induce the rapid translocation of cytoplasmic integrins to the surface of circulating leukocytes

D. To induce the increased expression of ICAM-1 and other adhesion molecules on endothelial cells

E. To attract leukocytes to the source of the cytokine in the tissue.

D. To induce the increased expression of ICAM-1 and other adhesion molecules on endothelial cells

MOST bacterial infections give rise to what type of

response?

A. a neutrophil-rich infiltrate

B. tissue edema

C. complement activation

D. local vasodilation

E. all of the above

E. all of the above

Which one of the following statements about metaplasia is NOT true?

A. Metaplastic tissues have a high risk of developing into cancer.

B. Metaplasia results from chronic tissue injury.

C. Only cells that are not capable of proliferation undergo metaplasia.

D. It is a common result of gastric reflux (reflux of stomach acid into the

esophagus)

E. Metaplasia usually results in a decrease in normal tissue function.

C. Only cells that are not capable of proliferation undergo metaplasia.

A myocardial infarct can result from which of the following?

A. A thrombus (blood clot) in a coronary artery, leading to tissue

ischemia

B. Asphyxia

C. An acute viral infection in cardiac myocytes

D. Excessive iron deposition in the heart

E. Leakage of cardiac enzymes from the myocytes

A. A thrombus (blood clot) in a coronary artery, leading to tissue ischemia