Acute Phase Reactants and Inflammation

• Systemic changes during inflammation involve acute phase reactants and other inflammatory mediators.

Acute Phase Reactants

• Proteins with altered blood levels during inflammation, either upregulated (positive) or downregulated (negative).

Positive Acute Phase Reactants

• Upregulated during inflammation assist in pathogen clearance, tissue repair, and immune modulation.
• Procalcitonin, C-reactive protein (CRP), ferritin, fibrinogen, serum amyloid A, hepcidin and thrombopoietin are positive acute phase reactants

Procalcitonin

• Secreted by thyroid C cells and other tissues during infection.
• Sensitive biomarker for bacterial infection and sepsis, with minimal elevation in viral infections.
• Assists in differentiating bacterial vs. viral infections; levels correlate with bacterial infection severity and systemic inflammation.
• Plays a small role in guiding decisions to initiate or stop antibiotics, distinguishing bacterial infections from viral infections to avoid unnecessary antibiotic use.
• Elevated in sepsis and severe bacterial pneumonia and is a precursor protein to calcitonin, primarily involved in calcium regulation.
• Triggers the production of procalcitonin directly or via cytokine signaling in bacterial infections, particularly sepsis.
• May help regulate bone resorption by inhibiting osteoclast activity during bacterial infections, especially those involving osteomyelitis.
• Helps maintain the integrity of bone during an infection, potentially limiting tissue damage caused by inflammation and bacteria.
• Supports immune cell function, such as the activation of neutrophils and macrophages, by helping to maintain normal calcium levels.
• Calcium influxes into the cells, triggering various signaling pathways that control their activation, proliferation, and function when immune cells like T cells, B cells, macrophages, and neutrophils encounter pathogens.

C-Reactive Protein (CRP)

• Direct marker of inflammation, part of the innate immune response, facilitates pathogen clearance by phagocytic cells (opsonization).
• Cytokines such as IL-6 are released when an infection, injury, or tissue damage occurs, prompting the liver to produce CRP
• Promotes atherosclerotic plaque formation escalating the inflammatory process, further exacerbating atherosclerosis in CAD
• Reflects systemic inflammatory process within the endothelium and Elevated CRP in this context correlates with the presence of coronary artery plaque and the likelihood of plaque rupture, which can cause a heart attack (MI).
• Elevated in coronary artery disease (CAD), hence elevation demands careful interpretation.
• In suspected acute myocardial infarction (MI) or CAD, measure troponin alongside CRP.
• Higher levels are linked to plaque rupture, promoting blood clot formation, potentially causing heart attack or stroke.

Ferritin

• Protein carrying iron and storing excess iron in a safe, non-toxic form and regulates iron homeostasis by controlling how much iron is available for cellular processes.
• Acute-phase reactant; levels increase during inflammation induced by pro-inflammatory cytokines.
• Sequestering iron away from pathogens decreases free iron availability, limiting pathogen growth during infection and nutritional immunity.
• Ensuring iron is readily available for immune cells for metabolic functions modulates the immune response.

Fibrinogen

• Plasma protein produced by the liver and critical in blood clotting.
• Levels increase during inflammation preparing for tissue repair and minimizing blood loss.
• Converted to fibrin by thrombin, forming a blood clot by sticking to injured tissues, creating a mesh-like wound-sealing structure.
• Correlates with erythrocyte sedimentation rate (ESR), indicates ongoing inflammatory process when elevated together
• Increases blood viscosity, causing red blood cells to settle more quickly, leading to elevated ESR but may not be as specific as just fibrinogen.
• Elevated also in thrombosis and increased bleeding risk.

Serum Amyloid A

• Secreted by the liver during inflammation in response to pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α.
• Acts as a chemotactic factor, attracting immune cells to inflammation sites of neutrophils, monocytes, and macrophages to areas of tissue damage or infection, enhancing clearing pathogens and tissue repair.
• Involved in lipid metabolism, transporting cholesterol to cells by binding and modifying function to HDL.
• Interacts with immune cell receptors (e.g., TLRs), triggering signaling pathways enhancing the immune response.
• Misfolding and aggregation in chronic conditions, leading to amyloid fibrils deposition in tissues and organs, causing amyloidosis.

Hepcidin

• Reducesthe availability of iron and elevates in long-term inflammatory responses, main regulator of iron metabolism.
• Regulates iron metabolism, ensuring availability when needed and preventing excessive accumulation.
• Inhibits iron absorption in the gastrointestinal tract and iron release from storage sites in the liver, spleen, and bone marrow.
• Elevated in inflammation triggers sequestration of iron away from the bloodstream to restricts iron supply to pathogens, limiting their ability to proliferate..
• Plays a central role in the development of ACD, elevated levels contribute to anemia in chronic diseases (e.g., CKD, cancer, obesity).

Thrombopoietin

• Increases platelet count during inflammation.
• Glycoprotein hormone produced by the liver and kidneys regulating platelet production from megakaryocytes in bone marrow.
• Key player in the hematopoietic system, stimulating megakaryocytes to increase platelet production.

Negative Acute Phase Reactants

• Downregulated during inflammation to redirect resources to manage inflammation and promote the immune response.
• Production downregulated by pro-inflammatory cytokines like IL-6, TNF-α, and IL-1.
• Albumin, prealbumin and transferrin are negative acute phase reactants

Albumin

• Most abundant plasma protein and synthesized in the liver.
• Maintains osmotic pressure, fluid balance, and transports substances.
• Production suppressed by pro-inflammatory cytokines during inflammation and reduced levels shift resources to immune response and tissue repair.
• Decreased can be a marker for systemic inflammation: often seen in sepsis, rheumatoid arthritis, liver cirrhosis, and kidney diseases.

Prealbumin

• Also known as transthyretin and synthesized by the liver.
• Transports thyroxine (T4) and retinol (vitamin A).
• Short half-life (2–3 days), levels used as an indicator of nutritional status and protein malnutrition.
• Synthesis downregulated during acute-phase response and liver shifts production to CRP and serum amyloid A
• Low levels can suggest the presence of acute or chronic inflammation. Levels are often used in critical care settings to monitor the nutritional status of patients.

Transferrin

• Decreases during inflammation, especially in acute bacterial infections.
• Glycoprotein transports iron and regulates iron homeostasis.
• Transports iron from the digestive tract and storage sites to tissues (e.g., bone marrow).
• Reduction in transferrin believed to be a way to limit iron available for pathogens; nutritional immunity.

Systemic Manifestations of Inflammation

• Fever, leukocyte count changes, ESR, increased pulse and blood pressure, and metabolic abnormalities are common.
• Fever is a 1–4°C elevation caused by pyrogens (cytokines, prostaglandins); treat with anti-prostaglandin medications (aspirin).

Leukocyte Count

• Elevated, usually 15,000–20,000 in acute inflammation; elevated in acute appendicitis.
• Count exceeding 100,000 suggests acute leukemia.
• Released from bone marrow in response to cytokines (IL-1, TNF-α).
• Lymphocytosis and eosinophilia typically seen in viral infections, especially atypical lymphocytes.

Erythrocyte Sedimentation Rate (ESR)

• Non-specific marker of inflammation, can also be elevated in rheumatoid arthritis and chronic diseases.

Inflammatory Response Symptoms

• Increased pulse and blood pressure, rigors, chills, anorexia, and malaise.
• Severe infections (septic shock): precipitous drop in blood pressure, DIC, and metabolic abnormalities.

Key Inflammatory Mediators (Cytokines and Chemokines)

Tumor Necrosis Factor (TNF-α)

• Production: Macrophages, dendritic cells, and T cells.
• Functions: Attracts leukocytes to inflammation sites; role in rheumatoid arthritis and inflammatory bowel disease.

Interleukin-1 (IL-1)

• Production: Macrophages, dendritic cells, fibroblasts, and endothelial cells.
• Increased levels in rheumatoid arthritis and inflammatory conditions.

Interleukin-6 (IL-6)

• Production: Macrophages, dendritic cells, and T cells.
• Elevated in rheumatoid arthritis and chronic inflammatory diseases.

Chemokines

• Released by virtually all cells in response to inflammation.
• Directs immune cells to inflammation sites.