ANTI-INFLAMMATORY EFFECTS OF HEPARIN-LIKE DRUGS: RELEVANCE TO COVID-19
Heparin is known to have anti-inflammatory effects both in the vasculature and in the airway, which could beneficially impact COVID-19-associated inflammation. Heparin binds to and modulates the activity of many proteins that mediate inflammation including IL-8, platelet growth factor 4 (PGF4), stromal-derived factor 1a, neutrophil elastase, P- and L-selectin, CD11b/CD18, major basic protein (MBP), and eosinophil cationic protein (ECP; 13, 47). The anti-inflammatory effects of heparin and its constituent heparan sulfate glycosaminoglycan fragments fall into two general mechanisms: 1) dampening of inflammation through interaction with proinflammatory proteins and 2) preventing adhesion and an influx of inflammatory cells to a diseased area.
There are innumerable studies that have demonstrated that heparin can dampen inflammation through its interaction with key inflammatory mediators. The proinflammatory transcription factor nuclear factor-κB (NF-κB), which has been found to be involved in the pathogenesis of SARS-CoV, the virus underlying the 2003 severe acute respiratory syndrome (SARS) epidemic (16), leads to the production of downstream inflammatory cytokines and other immune response proteins including tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-8 (13, 47). Heparin has been observed to directly dampen NF-κB signaling in LPS-stimulated human endothelial cells and human monocytes (21). Similarly, a synthetic heparin-like drug has recently been developed that neutralizes high mobility group box 1 (HMGB1; 5), a proinflammatory mediator that is known to play a role in the pathogenesis of viral infections (15). With respect to inflammatory cell infiltration, a phenomenon that has been observed pathologically in COVID-19 (2, 39), heparin can directly interact with vascular endothelial cells leading to reduced recruitment of the innate immune system and direct inhibition of neutrophil activation (13). More broadly, heparin has been shown to dampen inflammation in other preclinical models characterized by robust inflammation including pancreatitis (12) and sepsis (33).
Clinically, the use of heparin as an anti-inflammatory agent has shown limited evidence of benefit in human diseases including inflammatory bowel disease, asthma, reactive airways disease, and acute coronary syndrome (13, 24). Despite this clinical evidence, heparin has not been approved by the US Federal Drug Administration as a direct anti-inflammatory for any medical condition.