Cell injury,death,adaptations & acute inflammation Flashcards
Most common cell injury
Most common cause of hypoxia
Cells most sensitive to hypoxia
Cells least sensitive to hypoxia
Hypoxia
Ischemia
Neuron
Fibroblasts, then skeletal muscles
Major organelles affected by cell injury
- Nucleus
- Mitochondria (most commonly affected by reversible cell injury)
- Plasma membrane
- RER
Etiology
Initiating cause of the disease
Genetic ,environmental or both
Anorexia nervosa
Extreme self imposed food restriction
Hydropic change or vacuolar degeneration
Cellular swelling which is the earliest manifestation of almost all forms of injury to the cell
Small clear vacuoles which represent distended and pinched off segments of ER are present
Changes in the staining of cells progressing towards necrosis
The cytoplasm becomes more eosinophilic due to:
- loss of RNA
- Accumulation of denatured proteins
What are DAMPs
Damage associated molecular patterns
Include ATP (from mitochondria), uric acid (breakdown product of nucleus) and other molecules which are usually present within the cell and whose release is an indicator of severe cell injury. They trigger phagocytosis and cytokine release
Hypertrophy
Increase in cell size due to increased production of cellular proteins
Usually in permanent cells
Examples of hypertrophy
1. Pathologic hypertrophy (via Enlargement of heart 2. Physiologic hypertrophy Growth of uterus Body builders
Due to increased cellular protein production
Mechanisms of hyperplasia
- Growth factor driven proliferation
2. Stem cell derived (eg., liver cell regeneration)
Examples of physiological and compensatory hyperplasia
Physiological:
puberty, pregnancy, lactation
Compensatory:
partial hepatectomy, nephrectomy
Examples of pathological hyperplasia
- Hormonal (eg.,endometrial, prostatic)
- Viral warts
- Wound healing
- Bone marrow
- Lymphoid tissue
Examples of both hyperplasia and hypertrophy
Breast during puberty
And uterus during pregnancy
Atrophy
Mechanism
Loss of cell number and size
Mechanism:
1. Decreased protein synthesis
2. Increased protein degradation
Examples of physiological atrophy
- Thyroglossal duct and notochord
2. Uterine involution
Examples of pathological atrophy
- Arterial occlusion
- Inadequate nutrition
- Disuse
- Loss of innervation
- Pressure atrophy (eg., neoplasms causing compression)
Examples of epithelial metaplasia
1. In airways by cigarette smoke Pseudostratified to squamous 2. Urinary bladder by bladder stone Transitional to squamous 3. Barrett’s oesophagus by gastroesophagial reflux Squamous to columnar 4. Cervix due to acidity Glandular to squamous
Vitamin deficiency leading to squamous metaplasia
Vitamin A deficiency
Messenchymal metaplasia examples
Osseus metaplasia (eg.,testis) Eg., myositis ossificans (occurs in athletes as they are more prone to injury)
Necrotic cells have a glassy homogenous appearance relative to normal cells due to
Loss of glycogen particles
Ultrastructural changes of reversible cell injury include
- Cell membrane: Blebbing, blunting and loss of microvilli
- Mitochondria: swelling and small amorphous densities
- Cytoplasm: myelin figures (phospholipids from damaged cell organelles)
- ER: dilation, detachment of polysomes from it
- Nucleus: alterations with disaggregations of granular and fibrillar material
Fate of myelin figures
- Phagocytosed by other cells
2. Further degraded to FA. Calcification of such FA results in deposition of calcium rich precipitates
Types of necrosis
- Coagulative
- Liquefactive
- Fat: enzymatic and traumatic
- Caseous
- Fibrinoid
- Gangrene
Necrosis is because of two processes
- Denaturation of proteins
2. Enzymatic digestion of cells
Necrosis is characterised by electron microscope by
- Discontinuities in the plasma and organelles membranes
- Marked dilation of mitochondria with the appearance of large amorphous densities
- Intracytoplasmic myelin figures
- Amorphous debris
- Denatured proteins as aggregates of fluffy proteins
Coagulative necrosis which causes infarcts
The enzymes are also denatures with the structural proteins, hence blocking the proteolysis of dead cells.
Infiltrating leukocytes release lysosomal enzymes
Intensely eosinophillic cells with indistinct reddish nucleus are seen
Eg., Vessel obstruction ischemia except brain
Colliquative/ Liquefactive necrosis
Digestion of dead cells occurs, resulting in the transformation to a viscous fluid.
The necrotic material usually forms a creamy yellow pus
Eg.,
bacterial and fungal infections (enzyme release and leukocyte stimulation)
Hypoxic death of cells in CNS
Abscesses
The term cellular pathology was coined by
Rudolf Virchow
Gangrene
It is a pattern of cell death, applied to a limb (lower leg) that has lost its blood supply and has undergone necrosis (coagulative) involving multiple tissue planes
Wet gangrene
When a bacterial infection occurs with gangrene, there is more liquefactive necrosis
So liquifactive necrosis is considered as an example of wet gangrene while coagulative necrosis is considered as an example of dry gangrene
Casseous necrosis
Granuloma
The term caseous is derived from the friable white appearance of the area of necrosis
On microscopy, pink granular appearance
(Can be considered as a type of coagulative or combination of coagulative and liquifactive necrosis)
Focus of this necrosis is called granuloma
Fat necrosis - enzymatic
In acute pancreatitis, pancreatic lipase leak out of the damaged acinar cells and liquefy the membranes of fat cells in the peritoneum,
releasing TAG esters that are split.
That’s fatty acids combined with Ca to produce grossly visible chalky white areas (fat saponification)
Other examples are mesentery, omentum,…
Example of traumatic fat necrosis is breast
Fibrinoid necrosis
When complexes of antigens and antibodies are deposited in the walls of arteries
Type 3 or type 4 hypersensitivity.
This, together with the leaked plasma proteins , results in a bright pink and amorphous appearance in H and E strain called fibrinoid
Physiological examples of apoptosis
- Removal of excess cells during development
- Involution of hormone dependent tissues
- Cell turn over in proliferating cell populations
- Elimination of potentially harmful self reactive proteins
- Death of cells that have served is
Pathological apoptosis
- DNA damage
- Accumulation of misfolded proteins
- Infections (viral)
Morphological features of apoptosis
- Cell shrinkage: eosinophilic (normal-looking organelles which are tightly packed)
- Chromatin condenses peripherally into dense masses of various shapes (nucleus may split)
- Cytoplasmic blebs and apoptotic bodies
- Phagocytosis
Mitochondrial/ Intrinsic pathway of apoptosis upto initiator caspases
Cell injury (growth factor withdrawal/ DNA damage/ ER stress) ➡️
BCL2 family sensors ➡️
BCL2 family effectors (BAX,BAK)- Pro-apoptotic➡️
Mitochondrial membrane permeability decreases ➡️
Leakage of cytochrome c and other pro-apoptotic proteins ➡️
Initiator caspases (9)
Death receptor/ Extrinsic pathway of apoptosis
Receptor ligand interactions (Fas receptor / TNF receptor)➡️
Adaptor proteins called FADD (FAS Assoc. Death Receptor) ➡️
Initiator caspase activation (8 and 10)
Common steps of apoptosis mechanisms
Initiator caspases ➡️ Executioner caspases 3 and 6 (7 also) ➡️ : 1. Endonuclease activation ➡️ nuclear fragmentation 2. Breakdown of cytoplasm ➡️ Cytoplasmic bleb➡️ Apoptotic body ➡️ Phagocytosis
Anti apoptotic proteins (having 4 BH domains)
BCL2, BCL-XL and MCL1
Located in the outer mitochondrial membrane, cytosol and ER membranes
Prevents leakage of cytochrome c and other death inducing proteins
Pro apoptotic proteins (having first 3 BH domains)
BAX and BAK (p53 also)
On activation they oligomerise within the outer mitochondrial membrane, increasing its permeability
Thus leakage occurs
Regulated apoptosis initiators (have the 3rd BH domain) or arbiters of apoptosis
BAD, BIM , BID, Puma and Noxa
Their activity is regulated by sensors of cellular stress and damage
When activation causes apoptosis
The critical initiator caspase of intrinsic mechanism which is activated by the apoptosome (cytochrome c ➕ APAF-1)
Caspase-9
The process of apoptotic cell phagocytosis is called
Efferocytosis
Necroptosis or programmed necrosis
Mechanism
Starts similar to apoptosis (extrinsic) but the caspases are inactive, ending like necrosis
Appears like necrosis
Involves receptor interacting protein kinase 1 and 3 (RIPK -1 and RIPK-3)
Examples of necroptosis
- Formation of mammalian bone growth plate
- Cell death in steatohepatits, acute pancreatitis.
- Cell death in ischaemia-repurfusion injury
- Neurodegenerative diseases like Parkinson’s disease
- Backup mechanism of defence against viruses that encode caspase inhibitors (cytomegalovirus)
Important cells involved inflammation
In acute inflammation it is neutrophil
In chronic inflammation it is monocyte or macrophage
Exudate
Inflammatory edema
Specific gravity of exudate is more than 1.020
Rich in cells and proteins
LDH is high in exudate
Transudate
Non inflammatory
Specific gravity less than 1.012
Poor in cells and proteins
Low LDH
4 cardinal signs of inflammation
Rubor Dolor - pain Calor Tumour- swelling This was given by Celsus
The fifth sign given by Virchow was Functio laesa - loss of function
Vascular events of acute inflammation
- Earliest transient vasoconstriction
- Vasodilation and increased vascular permeability
- Stasis (of blood flow)
- Margination/ pavementing
Most critical event or hall mark of acute inflammation
The second step
Vasodilation and increased vascular permeability
Cellular events of acute inflammation which follows the vascular events
- Adhesion and transmigration
- Chemotaxis
- Phagocytosis
Mechanisms of increased vascular permeability
- Endothelial retraction in post capillary venules
- Endothelial cell contraction
- Direct endothelial injury
- Increased transcytosis
Endothelial cell retraction
Occurs in post capillary venules
Immediate transient response
Mediators: histamine, leukotrienes
Endothelial cell contraction
Occurs in venules and capillaries
Mediator: IL-1, TNF-alpha
Causes delayed sustained response
Direct endothelial injury
Mechanism acts on capillaries, venules and arterioles
Two types: severe and mild
Severe direct endothelial injury mechanism
By severe sunburn, chemicals
Endothelial cells will undergo necrosis and detachment
Leakage of fluid starts immediately
Continue till the new cells regenerate
Responsible for delayed sustained response
Mild direct endothelial injury mechanism
Endothelial cells undergo apoptosis
Leakage starts after some time
Responsible for delayed sustained response
Transcytosis
Passage of fluid through the channels which are formed in endothelial cell cytoplasm
Mediator: VEGF Vascular endothelial growth factor
Selectins (CD 62)
Three types: E (endothelium) ,P (platelet) and L selectin (leukocyte)
Their function is rolling
Complementary receptors of various selectins
- For E and P selectins it is Sialyl Lewis X modified glycoproteins located on the leukocyte
- For L selectins it is GLYCAM 1 - CD34
Involved in rolling
Immunoglobulins involved in cellular phase of acute inflammation
- ICAM-1 interacts with beta 2 integrin
- VCAM-1 interacts with beta 1 integrin
Both present on the endothelium
Involved in adhesion
Integrins involved in cellular phase of acute inflammation
- Beta 2 integrin (CD 2 / CD-18) (LFA 1 / MAC 1)
- Beta 1 integrin (VLA-4)
Present in the leukocyte
Involved in adhesion
CD 31
Also called PECAM 1
It brings out transmigration of the cellular phase of acute inflammation
Movement of leukocyte out of the endothelium
Mechanism of appearance of adhesion molecules
- Redistribution: for P selectin
- Induction:
ICAM-1, VCAM-1, E selectin
Fresh synthesis mediated by IL-1 and TNF-alpha - Increased avidity of binding:
Integrins
Increased number and strength of binding
Mechanism of appearance of p selectin
Redistribution
P selectin is present in the Weibel palade bodies of endothelium
During inflammation mediators like histamine, thrombin, PAF lead to the release of P-selectin to the surface of endothelium
Examples of exogenous chemotactic factors
Bacterial cell wall proteins like N Formyl Methionine
Examples of endogenous chemotactic factors
- C5a (a complement factor)
- LTB4 (a leukotriene)
- IL-8 (a interleukin)
Mechanism of chemotaxis
7 transmembrane G protein coupled receptors ➡️ increased cytosolic Ca ➡️ polymerisation of actin
➡️ chemotaxis
The receptors for recognition and attachment for phagocytosis
- Mannose receptors
- MAC 1 receptor
- Scavenger receptors
Which substances can act as opsonins
- Fc fragment of IgG
- C3b complementary protein
- Serum proteins like fibrinogen, CRP,…
Pyroptosis
Form of apoptosis accompanied by fever inducing cytokine IL-1 involving inflammosome and caspase 1
Thought to be the mechanism of microbial infection
Mechanism of pyroptosis
Microbial products that enter infected cells are recognised by cytoplasmic innate immune receptors
➡️ multiprotein complex called inflammasome is activated
➡️ activation of caspase-1 (also caspases 4 and 5)
➡️ activation of IL-1
➡️ inflammation (leukocyte recruitment and fever)
Ferroptosis
Caused when excessive intercellular iron or ROS overwhelm glutathione-dependent antioxidant defences
Lipid peroxidation ➡️ loss of membrane permeability
Cell death similar to necrosis, but regulated by specific signals and can be prevented by reducing iron levels
Ultrastructural features and examples of ferroptosis
Loss of mitochondrial cristae
Ruptured outer mitochondrial membrane
Variety of human pathologies like cancer, neurodegenerative diseases, stroke
Oxygen dependent killing
Most important
Also called oxidative burst
1. O2➡️ superoxide ion by NADPH oxidase
2. Hydrogen peroxide is formed which combines with chloride to form hypochlorite
Most effective bacterial killing system is the hydrogen peroxide halide system
Oxygen independent killing
Mediated by lysosomal enzymes like lysozyme, lactoferrin, BP1 (bacterial permeability increasing proteins)
LAD 1 or leukocyte adhesion
Autosomal recessive Defect in beta 2 integrin 1. Recurrent infections 2. Delayed separation of umbilical cord 3. Delayed wound healing
LAD 2
Mutation in sialyl Lewis X modified glycoprotein
Delayed rolling and adhesion
Recent infections
Chronic granulomatous disease CGD
X linked recessive (75%) or autosomal recessive (25%)
Deficiency of NADPH oxidase
Recurrent infection with catalase positive organisms
Test: Nitro Blue Tetrazolium test (NBT)
Chediak Higashi syndrome
Autosomal recessive
Mutation of LYST protein required for phagolysosome fusion
Emperipolesis
Intact viable cell within a cell The cell can exit without any structural or morphological change Seen in: 1. Rosai Dorfman syndrome 2. Hematolyphoid disorders like CLL 3. NHL
Chediak Higashi syndrome characteristics
- Fever
- Recurrent infections
- Albinism
- Deafness
- Thrombocytopenia
- Giant granules in neutrophils
Neutrophil extracellular traps NETs
Extracellular fibrillar mesh work produced by neutrophils at the site of infection
Provide a high concentration of antimicrobial substances at the infected site
Arginine is involved
Myelin figures are seen in
Both reversible and irreversible cell injury, though more in irreversible cell injury
Characteristics of irreversible cell injury
- Profound disturbances in cell membrane:
Becomes completely permeable, so cytosolic Ca increases➡️ activation of phospholipase, proteases,… - Severe mitochondrial damage
- 3 nuclear changes
- Release of lysosomal enzymes
Most common morphological features of irreversible cell injury
Flocculent amorphous densities in mitochondria (on electron microscopy)
In light microscopy it is the nuclear changes
Special features of coagulative necrosis
Most common type of necrosis
Most common organ affected by coagulative necrosis is heart
Examples of coagulative necrosis
Hypoxia
Severe burns
Zenker’s degeneration (patients with severe toxaemia like typhoid, affecting muscles like rectus abdominis and diagram)
Microscopy of coagulative necrosis
- Cell architecture/ outline is preserved
- Cells become eosinophilic
- Cells have glossy appearance due to loss of glycogen
- Cells have moth eaten appearance due to loss of organelles.
Examples of caseous necrosis
- TB (mycolic acid has high fat content)
2. Final infections like histoplasmosis, coccidiomycosis
Examples of fibrinoid necrosis
- Ascoff nodules
- Poly arteritis nodusa/ vasculitis
- Malignant hypertension
