The cytokines that drive the loop also act on the endothelium, the single cell layer lining every blood vessel. Endothelial cells express receptors for TNF-\(\alpha\), IL-1β, and IL-6. When those cytokines are present at high concentration, the endothelium shifts from a resting, barrier-forming state to an activated, pro-adhesive state. Adhesion molecules such as E-selectin, ICAM-1, and VCAM-1 are upregulated, so circulating leukocytes are captured and pulled into the tissue. At the same time, the intercellular junctions that hold endothelial cells together are loosened, and the cells contract. The result is a leaky barrier.
Plasma and protein move from the blood into the interstitial space. Clinically this appears as edema, falling blood pressure, and hemoconcentration. Because the same cytokines also induce tissue factor on endothelium and monocytes, the coagulation system is activated at the same time, producing microthrombi. The combination of leak and microthrombosis reduces perfusion to organs. The lung is often affected first because it receives the entire cardiac output and has a large capillary bed, so pulmonary edema and acute respiratory distress are common early events. The kidney, liver, and heart are also vulnerable because they depend on stable perfusion and are exposed to the same circulating cytokines.