Pathophysiology
II-27. Septic shock: inflammation, coagulation & endothelial dysfunction
敗血症性ショックにおける炎症・凝固障害・内皮機能障害
Endothelial Dysfunction in Septic Shock
- Healthy endothelium is anti-coagulant & anti-inflammatory
- Downregulated in sepsis: glycocalyx; PGI₂ & NO (inhibit platelet activation); t-PA (fibrinolysis activator); TFPI, thrombomodulin, heparan (anticoagulants)
- Upregulated in sepsis: P-/E-selectin, ICAM-1 (endothelium); ESL1/PSGL1 (monocytes) → leukocyte–endothelial interaction → activation + transmigration (diapedesis); cadherin loosening at tight junctions → edema + diapedesis
- Consequences: ↑permeability, edema, ↑O₂ diffusion distance, microvascular thrombosis
Coagulation–Immune Crosstalk
- Pathogens activate immune cells, endothelium and coagulation simultaneously
- Coagulation is initially useful: enzymatic cascade → antimicrobial peptides; thrombin activates immune-cell proteases; fibrin forms a physical barrier (neutrophil extracellular trap)
- Becomes tissue-damaging: coagulation blocks microcirculation → ↓tissue perfusion
- Sepsis upregulates coagulation + downregulates fibrinolysis (linked to innate immunity):
- Complement C5a → activates PAI → inhibits plasminogen activator → suppressed fibrinolysis
- C5b → tissue factor presentation on endothelium → coagulation cascade activation
- Net: ↑thrombin, ↑clot formation, ↓antithrombin/protein C/TFPI → microthrombi → DIC risk
Pro- & Anti-Inflammatory Processes
- SIRS (pro-inflammatory) balanced by CARS (compensatory anti-inflammatory response)
- Sepsis-induced immunosuppression:
- Anti-inflammatory cells (T-reg, immature PMN, MDSC, M2) → IL-10, TGF-β
- Lymph node: apoptosis of B-cells & follicular dendritic cells
- ↓monocyte HLA expression + ↑PDL1; T-cells express PD1 → PDL1–PD1 interaction → T-cell suppression/apoptosis; ↑T-reg/TH2 → ↓T-cell responsiveness
Acute & Chronic Consequences
- Normal course: pro-inflammatory peak → anti-inflammatory rise → resolution → healthy state
- Sepsis outcomes:
- Too strong → cytokine storm → lethal (e.g. COVID ARDS)
- Persistent inflammation → PICS (persistent inflammation, immunosuppression & catabolism syndrome)
- Prolonged immunosuppression → persistent infections (weeks–years) → death
- Catabolic upregulation → survive acute phase then cachexia → death
一問一答
▶What are the normal anti-thrombotic/anti-inflammatory properties of healthy endothelium?
Healthy endothelium is anticoagulant and anti-inflammatory.
▶What anticoagulant/anti-inflammatory factors are downregulated in sepsis?
Glycocalyx; PGI₂ & NO (inhibit platelet activation); t-PA (fibrinolysis); and TFPI, thrombomodulin, heparan (anticoagulants).
▶What adhesion molecules are upregulated in septic endothelial dysfunction?
P-/E-selectin and ICAM-1 on endothelium, and ESL1/PSGL1 on monocytes → leukocyte–endothelial interaction and transmigration (diapedesis).
▶How does cadherin loosening contribute to sepsis pathology?
Loosening of cadherins at tight junctions → edema and leukocyte diapedesis.
▶How is coagulation initially useful during infection?
The enzymatic cascade produces antimicrobial peptides, thrombin activates immune-cell proteases, and fibrin forms a physical barrier (neutrophil extracellular trap).
▶How does coagulation become tissue-damaging in sepsis?
Coagulation blocks the microcirculation, reducing tissue perfusion.
▶How does complement C5a affect fibrinolysis in sepsis?
C5a activates PAI, which inhibits plasminogen activator and suppresses fibrinolysis.
▶How does complement C5b promote coagulation in sepsis?
C5b drives tissue factor presentation on the endothelium, activating the coagulation cascade.
▶What is the net coagulation imbalance in sepsis, and what does it risk?
↑Thrombin and clot formation with ↓antithrombin/protein C/TFPI → microthrombi and risk of DIC.
▶What are SIRS and CARS in sepsis?
SIRS is the pro-inflammatory response, balanced by CARS (the compensatory anti-inflammatory response).
▶Which cells and cytokines mediate sepsis-induced immunosuppression?
Anti-inflammatory cells (T-reg, immature PMN, MDSC, M2 macrophages) releasing IL-10 and TGF-β.
▶How does the PDL1–PD1 interaction contribute to sepsis immunosuppression?
↓Monocyte HLA + ↑PDL1, with T-cells expressing PD1, leads to PDL1–PD1 interaction → T-cell suppression/apoptosis.
▶What happens in the lymph nodes during sepsis-induced immunosuppression?
Apoptosis of B-cells and follicular dendritic cells.
▶What is a cytokine storm and give a clinical example.
An excessively strong pro-inflammatory response that can be lethal — e.g., COVID-related ARDS.
▶What is PICS following sepsis?
Persistent Inflammation, immunosuppression and Catabolism Syndrome — a chronic consequence of unresolved sepsis.
▶How can prolonged immunosuppression after sepsis lead to death?
It allows persistent infections lasting weeks to years, which can ultimately be fatal.
▶How does catabolic upregulation after sepsis cause death?
Survivors of the acute phase can develop cachexia from sustained catabolism, leading to death.
▶Why are immune, endothelial, and coagulation systems activated together in sepsis?
Pathogens simultaneously activate immune cells, the endothelium, and coagulation, which then cross-talk and amplify one another.
▶What is the normal time course of inflammation resolution after infection?
A pro-inflammatory peak, then an anti-inflammatory rise, followed by resolution and return to a healthy state.
▶Why does loss of glycocalyx worsen septic endothelial dysfunction?
The glycocalyx normally maintains the anticoagulant/anti-inflammatory barrier; losing it promotes coagulation, leukocyte adhesion, and increased permeability.