Targeting Vascular Leakage for Novel Biomarker Diagnosis and Therapy of Severe Pulmonary Infections

Background: Persistent vascular leakage is a cardinal feature of major and severe infections, such as influenza and associated bacterial superinfections. These infections kill millions of individuals yearly, most commonly from complications affecting the vasculature such as acute respiratory distress syndrome and pulmonary edema. Newly emerged and re-emerging infections that threaten public health globally, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Ebola fever, also involve vascular leakage as an important factor of morbidity and mortality. We hypothesize that using therapy targeting on pathologically important vascular leakage regulators, morbidity and mortality from severe pulmonary infections can be improved by reducing excessive inflammation while not weakening host immune defence against secondary infections. Methods & Materials: By using monoclonal antibody and knockout mouse model of angiopoietin-like 4 (ANGPTL4), a novel regulator of vascular permeability, we investigated the effects of vascular leakage modulation in mouse models of influenza pneumonia and secondary pneumococcal pneumonia. To further validate our findings in animal and in vitro models, multi-center clinical studies involving hundreds of patient samples from hospitals in China, Singapore, France and Japan were also conducted. Results: Both viral and bacterial pulmonary infections stimulated the upregulation of ANGPTL4 expression in lung tissue, via a direct IL6-STAT3-mediated mechanism. ANGPTL4 enhances pulmonary tissue leakiness and exacerbates infiltration-induced lung damage. Anti-ANGPTL4 antibody therapy significantly reduced lung edema and protected lung tissue integrity. Surprisingly, while reducing excessive inflammation by restricting immune cell infiltration from blood vessels, anti-ANGPTL4 treatment also enhanced the function of innate immune cells, especially during secondary bacterial infection when the immune defense against bacteria was suppressed by primary influenza infection. Anti-ANGPTL4 treatment thus resulted in significant improvements on immune functions and lung tissue integrity in mice with secondary pneumococcal pneumonia. In our clinical sample analysis, ANGPTL4 has shown great potential as a biomarker to predict the severity of pneumonia, and guide the strategies to triage and treat pneumonia patients. Conclusion: Improving vascular integrity may provide an effective alternative or adjunctive strategy to combat severe pulmonary infections. ANGPTL4 is a promising target for designing diagnostic biomarker and therapeutic applications for the management of pulmonary infections.