Gram-negative pathohen-associated molecular patterns (PAMPs), such as LPS from the outer membrane of the gram-negative cell bind to pattern recognition receptors (PRRs) such as toll-like receptor-4 (TLR-4) found on the surface of defense cells such as macrophages. LPS can also bind to a LPS-binding protein that transports the LPS to a PRR called CD14 which, in turn transfers the LPS to TLR-4. The binding of LPS to TLR-4 sends a signal to the nucleus of the cell for transcription of genes coding for inflammatory cytokines. The macrophages subsequently synthesize and secrete inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (Il-1), interleukin-6 (Il-6), and interleukin-8 (Il-8), and platelet-activating factor (PAF). These cytokines bind to target effector cells in the area and influence their activity in some manner.

PAMPs and chemokines, such as IL-8, cause neutrophils to release proteases and toxic oxygen radicals for extracellular killing, the same chemicals they use to kill microbes, but these toxic chemicals are now being dumped onto the vascular endothelial cells to which the neutrophils have adhered during diapedesis. This results in damage to the capillary walls. Capillary damage and prolonged vasodilation and increased capillary permeability cause blood and plasma to leave the bloodstream and enter the tissue. This contributes to hypoperfusion. Prolonged vasodilation also leads to decreased vascular resistance and a resultant drop in blood pressure (hypotension). This contributes to hypoperfusion. Vasodilation and damage to the capillaries causes plasma and blood to leave the bloodstream and enter the tissue resulting in a decreased volume of circulating blood (hypovolemia). This contributes to hypoperfusion. Activation of the blood clotting pathway causes clots to form within the blood vessels leading to disseminated intravascular coagulation (DIC) that plug up blood vessels and prevent delivery of oxygen and nutrients to tissues and cells causing hypoperfusion. Vasodilation and capillary damage in the lungs causes the alveoli to become fluid filled (pulmonary edema) and prevents oxygenation of the blood. This is referred to as acute respiratory distress syndrome (ARDS). The combination of hypotension, hypovolemia, and DIC, results in hypoperfusion of oxygen and nutrients through the tissues and organs. ARDS prevents oxygenation of the blood. Without oxygen, cells switch to fermentation and produce lactic acid resulting in acidosis of the blood. Changes in the pH of arterial blood extracellular fluid results in the wrong pH for optimum cellular enzyme reactions leading to irreversible cell damage. Collectively, this can result in end-organ ischemia, irreversible shock, multiple system organ failure (MSOF), and death.