Cell Injury and Adaptation

Cell injury 
Causes are 

• Hypoxia 
• Infections
• Immunologic reactions
• Congenital disorders 
• Chemical injury
• Physical injury
• Nutritional imbalance 

Hypoxia

• Deficiency of oxygen due to redn in blood flow.

Types:

• Anoxic or hypoxic
• Anemic 
• Cardiopulmonary failure
• Histotoxic 

Infections

• Bacterial 
• Viral 
• Protozoal 
• Fungal
• Proteins like prions induced disease

Immunological reactions 

• Also called hypersensitivity reaction.
• They are protective to our body, but when excess they can have collateral tissue damage.
• Autoimmune diseases are targetted to the body cells causing their destruction.

Types:

• Type I
• Type II
• Type III
• Type IV 

Congenital disorders 

Disease due to trisomy

• Down’s syndrome
• Patau synrome
• Edward syndrome

Disorders of sex chromosome 

• Klinefeter’s syndrome
• Turner’s syndrome

Autosomal recessive 

• Osteogenesis imperfecta
• Cystic fibrosis
• Alkaptonuria
• Phnylketonuria
• Glycogen and lysosome storage disease

Autosomal dominant

• Familial hypercholesterolemia
• Marfan syndrome
• Ehler Danlos syndrome
• Neurofibromatosis

X linked recessive

• Lysch nyhan syndrome
• Chronic granulomatous disease

X linked dominant

• Fragile X syndrome
• Huntingtons disease

Physical agent

• Heat
• Cold
• Radiation
• Burn
• Crush
• Gunshot 
• Pressure changes

Chemicals 

• Acid
• Alkali
• Cyanide
• Poisons like arsenic, lead, mercury
• Alcohol
• Cigarette smoking
• IV drug abuse 

Nutrition

PEM 

• Anorexia nervosa
• Kwarshiorker
• Marasmus

Vitamin deficiency

• Scurvy, beri beri, pellagra
• Anemia
• Subacute combined degeneration (vit B12)

Nutrition excess

• Obesity and related disorders

Tissue response 

Cellular changes during cell injury

Reversible cell injury 

• ATP depletion
• Glycolysis and acidosis
• Na/H2O influx and cell swelling
• Ribosomal detachment
• Plasma membrane blebs and myelin figures are seen

• If oxygen is available and the other noxious stimuli are removed the cell can recover. If not it will go into irreversible stage.

Irreversible cell injury hallmarks 

• Severe membrane damage
• Marked mitochondrial dysfunction
• Lysosomal rupture and cell autodigestion
• Nuclear changes 
• Condensation/ pyknosis 
• Fragmentation/ karyorrhexis
• Disappearance / karyolysis 

Finally it will lead to the cellular death and inflammation.

Tissue death/necrosis 

Morphologic types 

• Coagulative necrosis- due to ischemia, cells are dead but cellular architecture is preserved. Eg in solid organs like liver and kidney.
• Liquefactive necrosis- necrosed cells are partially digested by lysosomal enzymes, and hence the cellular architecture is lost revealing cheesy material. Eg in brain , abscess and spleen.
• Casseous necrosis- combination of these two types. Seen in granulomas like TB.
• Fat necrosis- in fatty tissue due to the release of lipase.
• Fibrinoid necrosis- with the deposition of non specific protein. That results from acute immunologic injury. Eg Aschoff bodies in RHD,  Rheumatoid nodule, hypertensive vasculitis etc.

Gangrene-

1. it is the gross necrosis of a large tissue.

Dry gangrene- coagulative necrosis

Wet gangrene- liquefactive necrosis

Apoptosis

• Programmed cell death without inflammation.

Morphology:

• Cell shrink
• Nuclear condensation 
• Nuclear fragmentation
• Cellular fragmentation into apoptotic bodies 
• Phagocytosis

Pathway 

• Intrinsic
• Extrinsic 

Examples of apoptosis 

Physiological 

• Organogenesis 
• Menstruation
• Lymphocytes in the thymus 

Pathological 

• Viral hepatitis- councilman bodies
• Cystic fibrosis- pancreas atrophy

Serum markers 

• When the cells die, their enzyme comes out and level can be detected in the blood.
• This gives an important clue for the diagnosis of the disease.

Common markers are

• AST and ALT
• CKMB
• Amylase and lipase
• LDH
• Myoglobin 

Tissue adaptation to injury 

Atrophy 

• Decrease in organ size due to decrease in the number and the size of each cell.

Cause of atrophy are

• Disuse due to immobilisation
• Denervation atrophy
• Lack of hormone stimulus
• Malnutrition 
• Aging

Picture:

• Decreased cellular components
• Autophagolysosomes 

Hypertrophy

• Increase it the organ size due to the increase of the cell size.

Causes:

• Increased Mechanical demand like weight lifters or in hypertension (cardiac hypertrophy)
• Increased hormone stimulation e.g. gravid uterus , lactating breast.

It occurs in response to

• Growth factors
• Cytokines
• They lead to increased expression of the concerned genes and then causing increased protein synthesis.

Hyperplasia

• Increase in the organ size because of the increase in the number of cells.

Cell types:

• Labile cells
• Stable cells
• Permanent cells 
• Only stable and permanent cells can undergo hyperplasia.

Eg:

• After hepatectomy, the liver gains full size. Breast development in puberty etc.
• The stimulus are similar the hyperplasia.

Metaplasia

• The reversible change of one cell type to another.
• It is in response to chronic irritation.

Examples are

• Squamos metaplasia of the bronchail epithelium in the smokers
• Barret’s  esophagus
• The new type of epithelium come from the reserve cells that lie in the basal layer.
• It is not premalignant, but chances of malignancy is as high as 10-15 times than the normal.

Dysplasia

• The loss of cell differentiation is called dysplasia.
• It is the hallmark of malignancy.
• It is characterized by changes in cell shape, size and differentiation.

Examples 

• Oral leukoplakia
• Cervical dysplasia
• Solar keratosis 

Pathophysiology of Cell

Pathology 

• Patho- suffering 
• Logus- study 

Physiology 

• Physio- function 
• Logus- study 

Pathophysiology

• study of sequence of events from normal function to suffering.

Parts of cell 

• Membranes 
• Nucleus 
• DNA
• Euchromatin
• Heterochromatin
• Histone proteins   
• Nucleolus 
• Cytoplasm 
• Matrix
• Organelles
• Ribosomes
• Endoplasmic reticulum
• Mitochondria
• Golgi apparatus
• Lysosomes
• Peroxisome
• Cytoskeletal molecules 

DNA 

• Contains all genetic info.
• Arranged in fibers with the histone proteins, in 30 nm or 10 nm solenoid fibers.
• Condensed DNA at the time of cell division is called chromatin.

Made of

• Sugar- pentose sugar
• Nitrogen base – two types 
• Phosphate backbone 

Take part in two events

• Replication- structural importance 
• Transcription- functional importance

Any unwanted modification in the structure is the cause of genetic diseases and cancer.

RNA 

• Transcription product of DNA
• Carries message from the nucleus into the cytoplasm.
• The genetic info is read by ribosomes and that is decoded into the proteins.

Made of

• Deoxyribose sugar
• Nitrogen bases 
• Phosphate backbone

Three types:

• Ribosomal RNA- makes up the ribosome
• Messanger RNA- takes the info from the nucleus
• Transfer RNA – carries needed amino acids from the cyto into the nucleus.

Cytoplasm
Ribosomes:

• Small particles in the cytoplasm made of rRNA and protein 
• Either free or membrane bound with RER
• Human ribosomes are 80’s ribosome (bacterial are 70’s)
• Have two subunits, 60’s and 40’s
• Polysomes 

Function:

• Protein synthesis by traslation 
• Ribosomal detachment occurs at the time of cell injury is an important event, which limits the protein synthesis in the cell that leads to the irreversible injury and cell death.

Endoplasmic reticulum 
They are sac like structures attached to the outer nuclear membrane.
Types:

• Smooth- without endoplasmic reticulum
• Rough- with endoplasmic reticulum.

Functions:

• RER systhesizes protein for secretion, receptor proteins and lysosomes.

SER 

• Lipid synthesis and metabolism
• Drugs detoxification
• Glucose systhesis by glycogenolysis and gluconeogenesis 
• Release calcium in skeletal muscle 

Lysosome

They are simply the packets of the enzymes like acid hydrolases, nuclease, glycosidase, lipase protease etc in the cytoplasm.
Types:

• Primary lysosome
• Secondary lysosome 

Function:

• Intracellular digestion of the cell debris and endocytosed foreign body.

Pathological concerns:

• If some enzymes are deficient, then lysosomal storage disease like, Tay Sach’s disease( deficiency of hexaminidase, leading to accumulation of galglioside GM2 in the brain cells and mental retardation), Gaucher’s disease (deficiency of glucocerebidase),  Niemen Pick’s disease ( deficiency of sphingomyelinase) etc.
• Membrane rupture and release of the lysosomal enzymes lead to the intracellular digestion and plays an important role in the cell death and apoptosis.

Mitochondria 
It is double membrane structure, with the inner membranes are folded called as cristae, to increase the surface area.
It is the organelle that has its own DNA.
This DNA is only derieved from the mother, rest all are from the both.
So, any mitochondrial disease like Leber’s optic neuropathy, male infertility due to mitochondrial dysfunction is only inherited from the mother.
The part inside the inner membrane is called matrix, that has the dehydrogenase enzymes for the oxidative phosphorylation of NADH and FADH2 and generation of ATP.
So mitochondria is called as the powerhouse of the cell.

Mitochondria and relations to the pathology are

• Hereditary mitochondrial diseases like Leber’s optic neuropathy
• There is a protein called cyrochrome  c, that is an iron containing pigment uses in the oxidative phosphorylation. If this protein is released at the time of cellular injury, it directs the cell towards apoptosis.
• Mitochondrial dysfunction in the cell injury is a very critical step in the irreversible cell damage. Without mitochindria, the ATP’s out of a glucose molecule is just 2, with the production of lactic acid. And poor supply of ATP and acidosis will lead to the cell death very quickly.

Peroxisome 
They are a single membrane bound vesicles.
They contain the enzymes like peroxidase and catalase, that are related with the production and destruction of superoxide ions.
Their function are

• Provide free radicals during extracellular killing of foreign pathogens.
• Beta oxidation of long chain fatty acids
• Bile acid systhesis.

Pathology concerns 

• There are some genetic disorders like Zelweger syndrome, Refsum disease, infantile adrenoleukodystrophy  in which the peroxisomes are deficient and hence the long chain and branched fatty acids as well as the precursors of the bile acids are accumulated in the cell and causing cell dysfunction.
• The affected individual will have scanty myelin in CNS, progressive deafness and blindness, and MR, repeated infections and the death in ZS is as early as before 1st birthday.

Cytoskeleton 

Types:
1. microfillment- smallest one 7nm

• Actin
• They in conjunction with mysoin make the contractile unit
• They help in diakinesis in cell division.
• They form the core of the microvilli.

2. intermediate fillament

• Type i- Keratin- skin
• Type ii- Desmin- muscles, Vimentin in fibroblasts, myofibroblasts, and endothelium as well as vascular smooth muscles
• Type iii. Neurofillaments 
• Type iv- Lamins in the nuclear membrane.

3. micritubules- Largest 25 nm hollow tubes 

• Are attached with the ATPase motor molecule, that cleaves the ATP and provides the energy.
• The help in retrograde (Dyenin) and anterograde (Kinesis) transport. Speed is 200-400mm/d anterograde transport, and 4-200mm/d retrograde transport.

Pathology significance 

• Many virus like HSV and rabies as well as polio virus are stored in the ganglia, where they reach with the help of the retrograde transport.
• Cancer cells have augmented synthesis of these cytoskeletal molecules and hence fast cell division. So these are the targets of many anticancer drugs.
• In many diseases, there is deposition of these fibers. Like in cirrhosis, there is deposition of intermediate fillaments like keratin (mallory bodies), and Alzheimer's disease, there is deposition of the neurofibrillary tangles in the certain memory areas like hippocampus.

Cell adhesion molecules 

Calcium dependent

• Cadherin 
• Selectin

Calcium independent 

• Integrins 

Function

• Adheres the cells between each other and the basal lamina 
• Leucocyte migration into the tissue, integrin in the neutrophils binds to the selectin in the endothelial cell and gets in to the tissue.

Disease:

Antibodies to the desmosomes will cause pemphiguous vulgaris, and hemidesmosome will cause bullous pemphigoid.
Disruption of the cadherin molecule in the BM is the first step in the mets of the cancer.

Tissue
Group of similar cells for similar function.
Types:

• Epithelial tissue- origin ectoderm and endoderm
• Connective tissue- mesodermal in origin
• Nervous tissue- neuroectoderm and neural crest in origin
• Muscular tissue- origin mesoderm.

Pathological importance:

• Some disease involve single tissue and Some involve multiple
• Some  disease are primary to that tissue like muscular dystrophy, some are secondary or reactive like RHD.

Epithelial 

On the basis of striations 

• Simple 
• Striated

On the basis of cell structure

• Squamos 
• Columnar
• Cuboidal
• Transitional 

On the basis of cillia

• Cilliated 
• Non cilliated 

Muscular tissue 
It is the contractile tissue
It has actin and myosin, that glide on each other and hence they are contractile.
Types:

• Skeletal muscle
• Cardiac muscle
• Smooth muscle.

Connective tissue 

They are the supporting tissue.

Types:  

• Dense - bone, cartilage, dentine, enamel
• loose- dermis, adipose tissue etc
• Specialized connective tissue like blood, bone marrow, cartilage, adipose tissue.

Constituent 

• Cells- fibroblast, myofibroblast, chondroblast, osteoblast, adepocytes, and mast cells.  Histiocytes or Langerhans cells are blood borne macrophages that live in tissue.
• Extracellular matrix made of fibrillar protein (collagen, elastin, fibrillin, fibronectin), gel matrix made of preteoglycans and glycoproteins.
• Many  connective tissue diseases are targetted to them, like SLE, RA etc.

Main disease related with the bone 

• Rickets and osteomalacia- vitamin D deficiency
• Paget’s disease 
• Osteoporosis 

Types of collagen 

• Type I- in bones, cartilage, skin, sclera etc
• Disease is Osteogenesis imperfecta (mutation in gene coding type I cartilage)
• Type II- cartilage
• Type III- reticular fibers in the blood vessels.
• First formed collagen in the wound healing, that is later replaced by type I.
• Type IV is found only in the basal lamina, in the lamina propria.

Diseases are:

• Scurvy- inadequate hydroxylation of the preprocollagen
• Ehler Danlos syndrome
• Marfan syndrome- deffect in fibrillin gene.

Nervous tissue 
Types :

• excitable tissue ie neurones 
• Non excitable tissue like supporting cells.

Neurones:

• Unipolar
• Bipolar
• Multipolar

Glial cells:

• Astrocytes
• Oligodendrocytes
• Ependymal cells
• Microglia and 
• Schwaan cells 

CNS does not have fibroblasts. (clinical correlation is so brain tissue has no fibrosis after injury, but gliosis or hydrocephalous ex vacuo)


Disease concern 

• Gullian barre syndrome and multiple sclerosis- relation with myelin 
• Alzheimer's disease nerve degeneration with deposition of non specific protein material in the CNS
• Huntington’s disease degeneration of neurones in the caudate nucleus
• Parkinsonism neuronal degeneration in the nigrostiatal pathway

Types of Epithelium

Pathologic concerns with the blood 

Inflammation:

• 1st responder- neutrophil
• 2nd responder- macrophage, lymphocytes

Bone marrow malignancy
Immunity and related disorders
Anemia