Inflammation and Its Response

Inflammation

• Inflammation is a response triggered by damage to living tissues
• Purpose: to protect from infection and injury, to localize and eliminate the injurious agent and to remove damaged tissue components
• Consists of changes in blood flow, permeability of blood vessels, and migration of fluid, proteins, and white blood cells (leukocytes) to the site of tissue damage

Causes of Inflammation

• Microorganisms (viruses, bacteria)
• Physical agents (trauma, burns, radiation injury, frostbite)
• Chemicals (corrosive substances, acids, alkalis, oxidizing agents)
• Immunological responses (allergic, autoimmune reactions)
• Tissue death (lack of oxygen or nutrients)

Signs of Inflammation

• Redness (dilation of small blood vessels)
• Heat (increased blood flow)
• Swelling (edema, accumulation of fluid outside blood vessels)
• Pain (distortion of tissues, chemical mediators)
• Loss of function of the inflamed area

Types of Inflammation

• Acute inflammation (response lasts only a few days)
• Chronic inflammation (response of longer duration)

Acute Inflammatory Response

• Vascular changes:
  • Vasoconstriction (momentary)
  • Vasodilation (increase blood flow)
  • Increased permeability of blood vessels
• Cellular changes:
  • Phagocytes (neutrophils, monocytes)
  • Release of chemical mediators
  • Increased blood flow and permeability lead to exudate formation

Chronic Inflammation

• If the agent causing inflammation cannot be eliminated or healing process is impaired
• Repeated episodes of acute inflammation can also lead to chronic inflammation
• Examples: tuberculosis, rheumatoid arthritis, chronic lung disease

Diagnosis of Inflammation

• Tests:
  • C-Reactive Protein (CRP) level
  • Erythrocyte Sedimentation Rate (ESR)
  • White blood cell count### Lipid and Lipoprotein Analyses
• Renal failure can lead to increased serum triglyceride levels due to impaired removal of large molecular-weight constituents.
• Hypertriglyceridemia is often caused by an imbalance between VLDL synthesis and clearance in the circulation.
• Cholesterol can be estimated using colorimetric or enzymatic methods, such as the Salkowski reaction, which involves the formation of a red color with sulfate acid, and the Liebermann-Burchard reaction, which involves the formation of a green color with sulfuric acid.

Cholesterol Measurement

• The traditional lipid workup begins with the measurement of total serum cholesterol.
• Early analytic methods used strong acids, such as sulfuric and acetic acids, to produce a measurable color with cholesterol.
• The current reference method for cholesterol uses hexane extraction after hydrolysis with alcoholic KOH, followed by reaction with the Liebermann-Burchard color reagent.
• Enzymatic reagents have generally replaced strong acid chemistries in the routine laboratory.

Lipoprotein Measurements

• HDL and LDL are quantified based on their cholesterol content.
• The common lipid panel includes measurements of total, LDL, and HDL cholesterol, as well as triglycerides.

Liebermann-Burchard Method

• The method involves a sequence of reactions to measure cholesterol.
• Cholesteryl ester hydrolase cleaves the fatty acid residue from cholesteryl esters, converting them to free cholesterol.
• Cholesterol oxidase reacts with free cholesterol to produce hydrogen peroxide, which is then coupled with a chromogen to produce a colored compound.
• The intensity of the resulting color is proportional to the amount of cholesterol.

Salkowski Test

• The Salkowski test is a qualitative method for determining cholesterol.
• Cholesterol is dissolved in organic solvents, such as ether or chloroform, and then treated with strong acids, such as sulfuric acid.
• The oxidation of cholesterol produces a cherry-red color.

Phosphovanilin Method

• The Phosphovanilin method is a colorometric assay for lipid measurement.
• Lipids react with sulfuric acid to form carbonium ions, which then react with vanillin phosphate ester to produce a purple complex.
• The absorbance of the complex is measured at 530 nm, and the intensity of the color is proportional to the total lipid concentration.

Clinical Significance

• The normal range of total lipid levels in blood plasma is 400-700 mg/dL in fasting conditions.
• Hyperlipidemia is an elevated lipid level in the blood, which increases the risk of cardiovascular disease.
• Hyperlipidemia can be observed after a high-fat diet, and it is important to fast before lipid tests.

Disorders of Amino Acid Metabolism

Six Amino Acids Degraded to Pyruvate

• Alanine, tryptophan, cysteine, serine, glycine, and threonine are degraded to pyruvate.

Glycine Degradation

• Glycine is degraded to glyoxylate, which is then oxidized to oxalate.
• Oxalate can form crystals, which can account for up to 75% of all kidney stones.

Seven Amino Acids Degraded to Acetyl-CoA and/or Acetoacetyl-CoA

• Tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine, and threonine are degraded to acetyl-CoA and/or acetoacetyl-CoA.
• Some of the intermediates in tryptophan catabolism are precursors for the synthesis of other biomolecules, such as nicotinate, serotonin, and indoleacetate.

Phenylketonuria (PKU)

• PKU is a genetic defect in phenylalanine hydroxylase, which leads to elevated levels of phenylalanine in the blood.
• Phenylalanine hydroxylase requires the cofactor tetrahydrobiopterin, which carries electrons from NADPH to O2.
• Without treatment, PKU can cause severe intellectual disability.

Alkaptonuria

• Alkaptonuria is a genetic defect in homogentisate dioxygenase, which leads to the excretion of homogentisate in the urine.
• The oxidation of homogentisate turns the urine black.

Albinism

• Albinism affects the production of melanin, which is derived from tyrosine.
• Deficiency in the production of tyrosine leads to patches of unpigmented hair.

Four Amino Acids Converted to Succinyl-CoA

• Methionine, isoleucine, threonine, and valine are converted to succinyl-CoA.

Methylmalonic Acidemia

• Methylmalonic acidemia is a genetic defect in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonyl-CoA.
• Without treatment, methylmalonic acidemia can cause severe symptoms, including seizures, vomiting, and lethargy.

Branched-Chain Amino Acids

• The branched-chain amino acids, leucine, isoleucine, and valine, are not degraded in the liver.
• They are oxidized as fuels primarily in muscle, adipose, kidney, and brain tissue.

Maple Syrup Urine Disease

• Maple syrup urine disease is a genetic defect in the branched-chain α-keto acid dehydrogenase complex, which leads to the accumulation of the three branched-chain α-keto acids.
• Without treatment, maple syrup urine disease can cause abnormal development of the brain and death in early infancy.

Homocystinuria

• Homocystinuria is a disorder of methionine metabolism, which leads to the accumulation of homocysteine and its metabolites in the blood and urine.
• Homocystinuria can cause intellectual disability, seizures, and cardiovascular disease.### Cushing's Syndrome
• Affects 3 times as many women as men
• Can cause health problems such as:
  • Heart attack and stroke
  • Blood clots in legs and lungs
  • High blood pressure
  • Unhealthy cholesterol levels
  • Depression or mood changes
  • Memory loss or trouble concentrating
  • Insulin resistance and prediabetes
  • Type 2 diabetes

Hormones

• Parathyroid hormone (PTH):
  • Secreted by parathyroid glands in the neck region
  • Regulates blood calcium levels
• Insulin:
  • Lowers blood sugar levels
  • Stimulates metabolism of glucose, protein, and lipids
  • Produced in the pancreas
• Glucagon:
  • Raises blood sugar levels
  • Produced in the pancreas
• Erythropoietin:
  • Affects red blood cell production
  • Produced in the kidneys
• Renin and angiotensin:
  • Controls blood pressure
  • Regulates aldosterone production from adrenal glands
  • Produced in the kidneys

Trace Elements

• Copper (Cu):
  • Essential element in human growth and development
  • Important for oxidation and reduction reactions
  • Found in brain, kidney, heart, bone, and muscle
  • Daily requirement: 0.5-0.7 mg/day in children, 2-3 mg in adults
  • Sources: liver, walnuts, hazelnuts, legumes, shellfish, green vegetables, and milk
• Zinc (Zn):
  • Essential element in human growth and development
  • Stabilizes protein structures
  • Important for immune system
  • Found in skin, muscles, bones, prostate gland, semen, liver, and sac
  • Daily requirement: about 15 mg
  • Sources: meat, fish, milk, and dairy products
• Iron (Fe):
  • Essential element in human growth and development
  • Important for oxygen transport in the body
  • Found in hemoglobin and myoglobin structures
  • Daily requirement: 1 mg/day in men, 8 mg/day in women
  • Sources: liver, kidney, heart, offal, egg yolk, fish, oysters, beans, spinach, wheat, and oatmeal
• Cobalt (Co):
  • Essential element in human growth and development
  • Found in cobalamin (vitamin B12) structure
  • Important for erythropoiesis and nerve function
  • Sources: vegetables and fruits
• Chromium (Cr):
  • Important for glucose metabolism
  • Found in brewer's yeast, molasses, and whole wheat
• Selenium (Se):
  • Antioxidant properties
  • Found in glutathione peroxidase, iodothyronine deiodinases, and thioredoxin reductase structures
  • Important for thyroid hormone synthesis and metabolism
  • Sources: plant-based foods, animal products, and human milk

Congenital Metabolic Defects

• Disorders of carbohydrate metabolism:
  • Glycogen storage disease
  • G6PD deficiency
• Disorders of amino acid metabolism:
  • Phenylketonuria
  • Tyrosinemia
  • Maple syrup urine disease
• Disorders of fatty acid metabolism:
  • Urea cycle defects
• Lysosomal storage disorders:
  • Gaucher's disease
  • Niemann-Pick disease
• Disorders of peroxisomal function:
  • Zellweger syndrome