Abstract / Summary
Systemic inflammation in sepsis causes internal cell and tissue injury through mechanisms that remain incompletely understood. Secretory phospholipase A2 (sPLA2-IIA; hereafter, sPLA2), a potent inflammatory mediator whose circulating levels rise dramatically during sepsis, hydrolyzes membrane phospholipids in injured and dying cells, thereby releasing fatty acids and lysophospholipids that further amplify inflammation. Serum albumin—particularly a specific membrane-binding fraction (SFA)—normally acts as a cytoprotective scavenger of these lipid products, thereby maintaining membrane phospholipid homeostasis in concert with sPLA2. This perspective synthesizes nearly two decades of work demonstrating that the sPLA2–albumin interaction is a critical, underappreciated determinant of internal cell and tissue injury during systemic inflammation. As sPLA2 activity rises during sepsis, fatty acids generated from injured membranes progressively saturate albumin’s binding sites, inducing structural misfolding that abolishes its cytoprotective capacity and paradoxically enhances further sPLA2-mediated membrane degradation. Serial serum samples from ICU patients with sepsis revealed a statistically significant positive correlation between sPLA2 activity and albumin membrane-binding-site saturation, modifiable by nutritional intervention. Age-related albumin misfolding and oxidative stress are identified as important amplifying factors. The sPLA2–albumin axis represents a promising target for biomarker development and therapeutic intervention in critically ill patients.