Chapter 5: Sterile Inflammation in Sickle Cell Disease

Overview

Studies over several decades have characterized 3 major events (hemoglobin S [HbS] polymerization described in Chapter 2, vaso-occlusion discussed in Chapter 3, and hemolysis-mediated endothelial dysfunction discussed in Chapter 4) that drive the pathobiology of sickle cell disease (SCD).^1-4 Recent findings have identified sterile inflammation as another underlying phenomenon that contributes to the pathophysiology of SCD. Sterile inflammation involves the activation of innate immune pathways, in the absence of infection, in diverse vascular cells in response to the release of a variety of damage-associated molecular pattern molecules (DAMPs) from dying or damaged cells or tissues.^1,5,6 Several DAMPs and innate immune pathways that contribute to inflammation and end-organ damage in SCD have been identified.^1,5 They trigger disturbances in the innate immune system that appear to promote infection, acute systemic painful vaso-occlusive episode (VOE), acute chest syndrome (ACS), and chronic organ damage in SCD patients.^1,2,4,7-16 The improved understanding of these molecular pathways has also led to identification of new therapeutic targets to attenuate both acute and chronic complications of SCD.^1,3,9,17-19 This chapter serves to inform readers of the current understanding of the role and mechanism of sterile inflammation in SCD. The next section of this chapter describes hematologic findings that inspired recent studies to explore the role of sterile inflammation in SCD. The following section describes pathways and phenomena that have been found to contribute to sterile inflammation in SCD. We then describe how our current understanding of sterile inflammation is inspiring new avenues of therapy for SCD. Next, we discuss how insights in sterile inflammation are guiding contemporary research in SCD. Finally, we end the chapter with concluding remarks.

Footprints of Sterile Inflammation in SCD

VOE, ACS, and Chronic Organ Injury

Studies conducted in SCD mice and patients over the past 2 decades have identified several immunologic and hematologic abnormalities (clockwise in Figure 5-1 and described in the following text) that suggest a role for sterile (noninfectious) inflammation in acute and chronic pathobiology of SCD.¹ Occlusions in various vascular beds promote the development of acute systemic painful VOE, which is the primary reason for emergency medical care among SCD patients.⁴ Clinical evidence suggests that VOE is frequently a leading prodrome to ACS, particularly among adult patients. ACS is a severe acute lung injury (ALI) in SCD; it is one of the leading causes of mortality among this patient population.^4,15,20 ACS is associated with 3 major findings at diagnosis: hypoxia, multilobular pulmonary infiltrates, and acute anemia (decrease in hemoglobin [Hb]).¹¹ Infectious bronchopneumonia and bacteremia are also major risk factors for ACS.^11,16,21-27 Other causes include pulmonary vaso-occlusion and infarction, pulmonary fat embolism, and/or sudden decrease in Hb (acute hemolysis) in the absence ...