Poma Inflammation

Cell injury

 Cellular response: when cells are exposed to mild injurious agent or minor stress, they can respond by adapting to continue function. But if the stress exceeds the cells adaptive capacity, cell injury response occurs. Irreversible cell injury causes cell to be destroyed (necrosis) or induced to suicide (apoptosis)
 Causes of cell injury:
- physical: trauma, heat, cold, radiation, electricity and hypoxia
- chemical: extreme pH, free radicals, low or high oxygen
- biological: micro-organism, lack of growth factors, immune damage, nutritional imbalance
- immunological: autoimmune
- genetic: severe congenital malformation, subtle variation in genetic makeup that influence susceptibility
- nutritional: severe protein-calorie deficiencies, anorexia nervosa, and cholesterol and excessive lipids
 Types of cell damage:

 Reduced energy production: depletion of ATP occurs commonly during cell injuries, e.g. lack of oxygen, damage to enzyme in cytoplasm or mitochondria. This will reduce energy available for:
- enzyme that repair damaged DNA and protein
- ATP-driven membrane ion pumps causing ionic and osmotic homeostatic disruption. Sodium and water accumulate intracellularly leading to cell and organelle swelling. Reduced activity of membrane Ca2+ pump leads to influx of Ca2+ into cytosol and activating destructive calcium dependent enzymes
- protein synthesis and cause detachment of ribosomes from rough ER
 Damage to cell membrane: may occurs directly such as by free radical, hypoxia, or membrane-targeting bacterial toxins such as alpha toxin of clostridium perfringens, or failure of plasma membrane Ca2+ pump, phospholipases and decrease phospholipid synthesis. This causes:
- damage to plasma membrane and loss of cellular contention, osmotic balance, protein, enzymes, coenzymes, ribonucleic acid and influx of fluids and ions
- damage to transmembrane pumps directly or reduced function by decrease ATP
- injury to lysosomal membranes resulting in leakage of their enzyme into cytoplasm and digestion cellular components (autolysis)
- decrease in content of membrane phospholipids due to activation of phospholipases and decreased synthesis of phospholipids due to lack of ATP
- damage of mitochondrial membrane leading to formation of nonselective high-conductance channels in the inner mitochondrial membrane (mitochondrial permeability transition) and removes the transmembrane potential needed for oxidative phosphorylation. Leakage of cytochrome c also triggers apoptosis and hinder energy production.
 Increase cystolic calcium concentration: reduced activity of Ca2+ pump allow influx of Ca2+ and activates destructive calcium-dependent enzymes
- ATPase
- Phospholipases
- Proteases
- Endonucleases
 Damage by free radicals: reactive radicals release energy through reaction with adjacent molecules. Accumulation is known as oxidative stress and can generate cell injury
- generated by diverse injurious agent and stressors including ionization irradiation (split water to generate OH), enzymatic metabolism of chemical or drugs, normal metabolism
- free radical attack double bonds of fatty acids in membranes (lipid peroxidation), oxidizing amino acids residue side chains in proteins, reacting with thymine in nuclear and mitochondrial DNA.
- Chain reaction (autocatalytic)
- Cells have defense systems such as antioxidants, e.g. vit E and A for membrane and C and glutathione in cytosol, enzymes such as catalase, superoxide dismutases and glutathione peroxidases. But oxidative stress can overwhelming defense capacity.
 Other damages:
- protein damage by glycation or targeted for degeneration, detachment from cell membrane
- DNA damage by ionizing radiation, UV radiation, chemical agents, genetics, dietary (vit B12 or folate deficiency)

Response to cell injury

 Heat shock factors: transcription factors that specifically induce the expression of heat shock proteins which are molecular chaperones that assist in repair (refolding) of damaged proteins
 Stress kinases: kinases such as p38 MAP kinase and Jun N-terminal kinase that initiate signaling cascade that co-ordinate a cell’s response to damage
 Types of signal proteins: pathway proteins that is activated corresponding to specific injury
- p53: senses DNA damage and initiates other a halt to cell division (to allow repair) or cell death by apoptosis (not repairable)
- BMF: involved in the response to damage to actin cytoskeleton
- Bim: involved in response to microtubule damage
- Bad: involved in cell stress due to inadequate stimulate by growth factors
 Adaptive response:
- Hypertrophy: cells respond to increased functional demand and stimulation by increase number of cells. The process result from stimulation of intracellular signaling pathways and activate of many cellular genes.
- Hyperplasia: increase cell numbers from both division of cells, division of stem cells locally in the tissue, or division of stem cells hat emigrate into the adapting tissue from bone marrow.
- Atrophy: cells respond to reduced functional demands, nutrients supply, growth factors or stimulation through nerves by cell shrinkage. This involves proteolytic systems including lysosomes digesting cellular content (autophagy) and protein destruction through ubiquitin-proteasome pathway
- Metaplasia: reversibly change from one cell type to another as a means of adaptive substitution of cells that are sensitive to stress by cell types better at withstanding adversity. It involves the reprogramming of stem cells that resides in normal tissue by signal growth factors and extra cellular matrix components.
 Ubiquitin: molecules that tags the protein for destruction by proteases.
 Reversible cell injury: response depends on type of injury, duration, severity and on the type of cell (i.e. different adaptability, genetics). Some morphological patterns:
- cellular swelling: loss of function of plasma membrane ion pump and small clear vacuole may be seen
- hydropic change: failure of ion pumps in ER membrane and pinched off segments of ER appear in cytoplasm
- fatty change: occurs after hypoxic or toxic injury to cell that utilized fat metabolism, such as the hepatocytes and myocardial cells. Lipid vacuoles appear in cytosol.
 Necrosis: passive form of cell death in which cells are killed by overwhelming damage
- affects large number of cells in a tissue
- not require energy
- often accompanied by lysosomal membrane rupture and leakage of enzymes that digest cellular components (autolysis)
- cytosolic content leak into extracellular space inducing inflammatory response
- uncontrolled, messy and always pathological
- featureless due to denaturation and digestion of proteins
- usually necrotic cells fragment are removed within days by phagocytosis but if not, it can cause precipitation of calcium called dystrophic calcificaion
 Karyorrhexis: fragmentation of chromatin
 Pyknosis: occurs prior to karyolysis, the chromatin shrinks into a dense mass at the margin of nucleus
 Karyolysis: fading of chromatin due to activity of DNAse enzyme
 Apoptosis: programmed cell death or suicide
- induced following cell stress or injury where a cell has the time and energy required to execute a suicide routine
- requires energy hence first step in apoptosis is the destruction of cellular machinery that uses ATP such as PARP
- common after DNA damage, inadequate growth factor supply, mild hypoxia, or accumulation of damaged proteins
- also plays a role in eliminating, unwanted or wrongly placed cells during embryogenesis, self-reactive immune cells, neoplastic cells or virus infected cells
- membrane bound blebs containing cytosolic contents and organelles break off the cell and are phagocytosed by neighbouring cells.
 Caspase: a cascade of enzymes that mediate the events of apoptosis. Caspases activate each other by proteolytic cleavage which removes inhibitory domains. The executioner caspases (caspase 3) digest cellular proteins and activate other enzymes such as nucleases
 Two pathways of apoptosis
- extrinsic: specific extracellular signaling molecules that belongs to the TNF family bind to death receptors on the surface of cell and activate regulatory caspases such as caspase 8 that in turn activate caspase 3 to induce cell death
- intrinsic: localized changes induced by insufficient availability of growth factors, damage to DNA and cytoskeleton, or substances release such as cytochrome c from mitochondria activate a regulatory caspase known as caspase 9. Caspase 9 cleaves and activates executioner caspases.

Environmental and Nutritional pathology

 Toxicant: substance that can injure cells, organs or whole organism.
- effect depending on rate and quantity absorbed
 Toxin: subset of toxicants that is produced by living cells or organisms. Thye are nearly alwaus proteins
 Xenobiotic: substances that are foreign to a given biologic system (e.g. substance not found in humans). After absorption, xenobiotics are distributed to various organs. Many xenobiotics are lipophilic and can penetrate lipid bilayer. To allow excretion, lipophilic xenobiotics must be metabolized into hydrophilic metabolites.
- phase I reaction: polar functional group added through hydrolysis, reduction or oxidation (mainly. Enzymes involved are cytochrome P450 enzymes which operate within the smooth ER of liver and other tissues
- phase II reaction: primary metabolites of phase I reaction are combined with endogenous substrates such as glucuronic acids. This produce the conjugate of the primary metabolite that are water soluble and readily excreted
 Toxicity: measure of the biological effect of toxicant at each dose often shown by a doses-response curve.
- threshold levels: level of dosage needed in order to have an effect. It can be used to to establish permissible occupation expose level for toxins
- ceiling effect: maximum biological effect a toxicant can reach
 Tobacco smoke:
- multiple carcinogens that damage DNA and increase likelihood of cancer.
- formaldehyde and nitrogen dioxide that cause cell injury
- increase likelihood of atherosclerosis and peptic ulcer disease
- contains CO which impairs the release of O2
- alkaloid nicotine that crosses the blood brain barrier and stimulates nicotinic receptor causing addition
 Alcohol: ethanol is metabolized to acetaldehyde by alcohol dehydrogenase, cytochrome P450 and catalase. Acetaldehyde is then converted into acetic acid by aldehyde dehydrogenase
- alcohol and its metabolites can cause cell injury and inflammation and fibrosis
- increased incidence of cancer
- alcohol inhibits enzyme that detoxify carcinogens and acetaldehyde is a tumour promoter
 Ionizing radiation: damage of radiation on boduy depends upon dose, duration, mode of exposure, cell lineage (adaptability) and amount of cell division
- Rads: a measure of the absorption of energy per gram of tissue
- Rem: the standardized biological effect of radiation on tissue
- Short duration result in acute radiation syndrome
- Long term exposure is fibrosis of tissue and increased incidence of cancer. This is due to radiation-included genetic instability
 DNA damage: Cell lineages such as haemopoietic cells, germ cells and gut/skin epithelium are especially susceptible to ionizing radiation. DNA damage occurs with lower doses and DNA strands breaks, formation of DNA protein cross-links and free radical generated by radiolytic cleavage of water. DNA damage is sensed by the cell and may lead to pa pause in the cell cycle to allow repair or apoptosis.
 Ultraviolet radiation: causes inflammation, melanocyte hyperplasia (tannin), loss of collage, skin cancer and premature aging of skin.
- Injury is caused by formation pf pyrimidine dimers in DNA, mutations of oncogenes and tumour suppressor genes, generation of reactive oxygen species from UV-damaged melanin and activation of UV response pathway including Ras and p53 signaling.
 Malnutrition:
- Marasmus: insufficient food intake to meet body’s requirement leading to severe muscle wasting and loss of subcutaneous fat. Protein is used preferentially in acute marasmus. Eventually malnourished patients develop impaired immune response, wound healing and reduced heart and lung function, and multiple organs failure leading to death.
- Kwashiorkor: inadequate protein intake causing serum protein concentration reduction and edema. Subcutaneous fat is usually spared.
 Obesity: disorder of energy balance. Increased likelihood of CV disease, diabetes and likelihood of death. Intra-abdominal fat causes a greater risk of CV disease than subcutaneous fat.
- balance is regulated by leptin (fat cells) and ghrelin (stomach)

Acute inflammation:

 Inflammation: the body’s response to tissue injury in a sequence of event involving blood vessel dilation, migration of leukocytes into injured tissues. Steps of inflammation is similar irrespective of type of tissue but outcome and clinical manifestation depends on nature, intensity and duration of agent and tissue affected.
 Triggers of acute inflammation:
- Infections, e.g. microbial toxins
- Trauma, e.g. blunt and penetrating
- physical and chemical agents, e.g. thermal injury
- tissue necrosis (most potent)
- foreign bodies, e.g. splinters
- immune reactions, e.g. hypersensitivity reactions
 First step of inflammation: following tissue injury, pro-inflammatory substances are released form injured and necrotic cells that activate local macrophages and endothelial cells.
 Second step: activated endothelial cells then produced inflammatory cytokines, prostaglandins and NO to vasodilate and increase permeability of blood vessels walls.
 Third step: blood flow is increase to the damaged tissue (hyperaemia) and increased exudation of protein-rich fluid into the inflamed tissue. Accumulation of fluid is termed oedema. The fluid exudate contains protins including antibodies, fibrinogen, kinin and plasmin cascade which act as important chemical mediators.
 Fibrinogen: the substrate that is enzymatically converted into fibrin which acts as a glue to seal damaged blood vessels and stabilize damaged tissue. Fibrin accumulates on epithelial surface where it becomes compacted by organ movement into dense fibrinoue exudates.
 Stasis: the slowing blood flow due to loss of fluid from the vessels and increasing viscosity.
 Margination: sequentially to stasis, leukocytes are found to accumulate near edges of blood flow along the vascular endothelium (especially for post-capillary venule)
 Fourth step: the increase in the expression of cell adhesion molecules.
- Expression of endothelial selectin molecules that bind to glycoproteins receptors on the surface of neutrophils hence slowing them down and cause they to adhere and roll along the vascular wall.
- Integrin molecules on neutrophil is increased and these bind to ligands known as addressin on the endothelial cells which stops the rolling the neutrophil completely.
 Fifth step: diapaedesis occurs where the neutrophils move between endothelial cells by inserting cell process into junctions between cells and eventually traverse the basement membrane and into the extra vascular space.
 Sixth step: as neutrophils move into tissues, they are become activated by multiple signals including chemokines, endothelial cell surface molecules, interleukin-1 and Tumour Necrosis Factor–alpha that are released from damaged tissue, activated endothelial cells and from other leukocytes.
- for example: TNF-alpha -> TNF receptor -> NFkB transcription factor -> genes -> neutrophil adhesion and diapaedesis
 Seventh step: chemotaxis of neutrophils toward injured tissue. Factors include exogenous substance such as bacterial products that possess an N-formyl-methionine terminal amino acid and/or endogenous such as leukotrienes, chemokines (IL-8) and compounds of complement system. This is achieved by chemotactic factors binding to specific seven-transmembrane G-protein coupled receptors on leukocytes, and through several steps that increase actin polymerization at head edge of the cell cause the extension of filopodia toward injury site.
 Eighth step: neutrophils attack source of inflammation but are limited in their killing potential. Necrotic neutrophil further release vasoactive, chemotactic and damaging substance (pro-inflammatory factors) and recruit secondary leukocytes.
- neutrophil survival is promoted by hypoxia through stimulated HIF system and NFkB and transcription of survival factors. Apoptosis occurs in normal oxygen
 Pus: mixture of dead neutrophils, infection, tissue debris and bacterial bodies in an inflammation
 Ninth step: acute inflammation is terminated when the offending agent is eliminated and secreted mediator factors are reduced. Anti-inflammatory mechanism exists to control inflammation response.
 Clinical manifestation of acute inflammation:
- local effects: redness, swelling, heat, pain, loss of function
- systemic effects: pyrexia (fever) mediated by inflammatory mediators such as IL-1 and TNF alpha released by endothelial cells and macrophages; leukocytosis; increased production of acute phase proteins involved in inflammation by liver; increased production of glucocorticoid steroid hormone
 Disadvantage of acute inflammation: the reason behind important disease such as rheumatoid arthritis, atherosclerosis, hypersensitivity reaction to toxins etc. Repair by fibrosis may lead to disfiguring scar and intestinal obstruction or limit mobility of joints.
- Anti-inflammatory drugs aims to minimize the harmful effects of inflammation without interfering with its benefits.

Chronic inflammation:

 Chronic inflammation: prolonged inflammation leading to participation of secondary leukocytes such as lymphocytes, monocytes, eosinphils etc. Leukocytes signal to each other and other cell types such as fibroblasts and endothelial cells to co-ordinate the inflammatory response.
 Macrophages: the multi-cellular fused form of monocytes with greater phagocytic and killing potential than neutrophils. After 24 hours, these are the dominant cell types in an inflamed tissue.
 Granuloma: a center or focus of chronic inflammation with a core of necrosis and also microscopic aggregation of macrophages that have fused into larger epithelium-like cells (epithelioid macrophages), surrounded by a collar of lymphocytes. Seen in tuberculosis.
 Healing: the body’s attempts to restore the original structure and function of an injured tissue, i.e. attempt to achieve resolution.
 Two parts of healing:
- cleaning up mess generated by injury and inflammation
- Rebuilding structure and function of tissue that was destroyed
 First part of healing:
- ideal situation, all messy exudates (dead cells etc) are completely removed by macrophages
- if mess or ECM scaffold is beyond restoration, response termed repair is underwent where the cell converts the mess into viable stable tissue
- during repair, process called organization takes place in which macrophages secrete growth factors such as Fibroblast GF and vascular endothelial growth factor that encourage the in-frewoth of fibroblast to lay down collagen and endothelial cells to form new vessels for nutrient, protein and oxygen.
 Granulation tissue: repairing tissue that contains many active fibroblasts and new blood vessels. It is then remodeled by regression of vessel and reorganization of collagen fibers into fibrous scar in a process called fibrosis (formation of fibrous tissue).
 Fibrous scar: an unwanted outcome of tissue injury as they represent loss of pre-existing functional tissue and hinder remaining functional one. E.g. scar tissue of myocardium is a permanent burden.
 Second part of healing:
- regeneration: process of replacing the parenchymal cells within the tissue that have been destroyed, i.e. hepatocytes in liver. This involves the proliferation of stems cells derived from within the tissue and the bone marrow.
- Regeneration most common in tissue with continual turnover of parenchymal cells such as skin and gut.

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