A father brings his 3-year-old son to the pediatrician because he is concerned about his health. He states that throughout his son's life he has had recurrent infections despite proper treatment and hygiene. Upon reviewing the patient's chart, the pediatrician notices that the child has been infected multiple times with S. aureus, Aspergillus, and E. coli. Which of the following would confirm the most likely cause of this patient's symptoms?

Negative nitroblue-tetrazolium test

Increased IgM, Decreased IgG, IgA, and IgE

Positive nitroblue-tetrazolium test

Normal dihydrorhodamine (DHR) flow cytometry test

Increased IgE and IgA, Decreased IgM

A 7-year-old boy with asthma is brought to the physician because of a 1-month history of worsening shortness of breath and cough. The mother reports that the shortness of breath usually occurs when he is exercising with his older brother. His only medication is an albuterol inhaler that is taken as needed. The physician considers adding zafirlukast to his drug regimen. Which of the following is the most likely mechanism of action of this drug?

Antagonism at leukotriene receptors

Antagonism at muscarinic receptors

Blockade of 5-lipoxygenase pathway

Inhibition of mast cell degranulation

Inhibition of phosphodiesterase

Two days after being admitted for acute myocardial infarction, a 61-year-old man has sharp, substernal chest pain that worsens with inspiration and improves when leaning forward. Cardiac examination shows a scratchy sound best heard over the left sternal border. Histopathological examination of the infarcted myocardial tissue is most likely to show which of the following findings?

Granulation tissue with macrophages

A 4-year-old Caucasian boy is brought by his mother to the pediatrician with a red and swollen elbow. He was playing outside a few days prior to presentation when he fell and lightly scraped his elbow on the sidewalk. He was born at 34 weeks' gestation and was in the neonatal ICU for 2 days. His temperature is 102.1°F (38.9°C), blood pressure is 105/65 mmHg, pulse is 110/min, and respirations are 20/min. On exam, he has a swollen, erythematous, fluctuant, and exquisitely tender mass on his right elbow. There is expressible purulence coming from his wound. A peripheral blood smear in this patient would most likely reveal which of the following findings?

Neutrophils with abundant peroxidase-positive granules

Absence of dark blue cytoplasmic staining upon nitroblue tetrazolium administration

Neutrophils with peroxidase-negative granules

Neutrophils with pale cytoplasm without granules

Macrocytic erythrocytes and acanthocytes

Chemical mediators of inflammation for USMLE Step 2 CK: High-Yield Pathology Lessons

Vasoactive Amines & Plasma Proteases - The First Responders

Histamine & Serotonin (5-HT): Pre-formed in granules.
- Source: Mast cells (histamine), Platelets (both).
- Action: Arteriolar dilation & venular permeability ↑. Released rapidly in response to IgE, C3a/C5a, or trauma.
Plasma Proteases (Liver-derived): Activated in a cascade.
- Hageman Factor (Factor XII) is the key initiator upon contact with collagen or basement membranes.

⭐ Bradykinin is a key mediator of pain (dolor) in acute inflammation, in addition to causing potent vasodilation and increased permeability.

Hageman Factor XIIa activation cascade and inflammation

Arachidonic Acid Metabolites - The Cascade Crew

Source: Cleaved from cell membrane phospholipids by Phospholipase A₂.
Two Major Pathways: Cyclooxygenase (COX) and Lipooxygenase (LOX).

Arachidonic Acid Pathway with Inhibitors

Prostaglandins (PGs): Mediate vasodilation, pain, and fever (PGE₂).
Thromboxane A₂ (TXA₂): Opposes PGI₂; promotes platelet aggregation and vasoconstriction.
Leukotrienes (LTs):
- LTB₄: Potent chemotactic agent for neutrophils. 📌 B for Brings neutrophils.
- LTC₄, LTD₄, LTE₄: Cause bronchospasm and increased vascular permeability.

⭐ Aspirin irreversibly inhibits COX-1 and COX-2, leading to a prolonged antiplatelet effect (lasting the life of the platelet, ~7-10 days). This is distinct from other NSAIDs, which are reversible inhibitors.

Cytokines & Chemokines - The Master Conductors

Cytokines: Small proteins mediating immunity and inflammation.
- Pro-inflammatory (Systemic Effects):
  - TNF-α, IL-1: Secreted by activated macrophages. Induce fever, fatigue, and cachexia. Upregulate endothelial adhesion molecules (selectins, ICAM/VCAM).
  - IL-6: Also from macrophages. Stimulates acute-phase protein production (e.g., CRP) in the liver.
- Anti-inflammatory:
  - IL-10, TGF-β: Inhibit cytokine production, promoting resolution and repair.
Chemokines: A type of cytokine that directs leukocyte migration (chemotaxis).
- IL-8 (CXCL8): Potent neutrophil chemoattractant.
- MCP-1 (CCL2): Attracts monocytes.
- Eotaxin (CCL11): Attracts eosinophils.

⭐ Systemic Inflammatory Response: TNF-α, IL-1, and IL-6 drive the systemic effects of inflammation, including fever (acting on hypothalamus), leukocytosis (bone marrow), and the acute-phase response (liver). In chronic disease, TNF-α mediates muscle wasting and cachexia.

Inflammation: Chemical Mediators and Cellular Response

Reactive Species & Others - The Odd Jobs Squad

Reactive Oxygen Species (ROS): Generated by phagocyte NADPH oxidase to destroy microbes.
- Key species: Superoxide ($O_2^{•-}$), hydrogen peroxide ($H_2O_2$), and hydroxyl radicals ($•OH$).
- Can cause significant tissue damage.
Nitric Oxide (NO): A potent, short-lived vasodilator.
Platelet-Activating Factor (PAF): Induces vasodilation, bronchoconstriction, and increases vascular permeability.

⭐ Nitric Oxide has a dual role: At low levels, it promotes vasodilation. At high levels, produced by iNOS in macrophages, it becomes microbicidal.

Reactive Oxygen Species Generation in Neutrophils

High‑Yield Points - ⚡ Biggest Takeaways

Histamine from mast cells drives early vasodilation and ↑ vascular permeability.

Prostaglandins (especially PGE₂) mediate fever and pain; Leukotrienes (LTB₄) are key for chemotaxis.

Key cytokines TNF, IL-1, and IL-6 orchestrate the systemic acute-phase response, including fever.

Complement C5a is a potent neutrophil chemoattractant; C3a and C5a also act as anaphylatoxins.

Bradykinin is a primary mediator of pain and increased vascular permeability.

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play