Triggering factors of
Acute Chest Syndrome (ACS) is a leading cause of death in patients with
Sickle Cell Disease (SCD) and targeted
therapies are limited.
Chlorine (Cl2) inhalation happens frequently, but its role as a potential trigger of ACS has not been determined. In this study, we hypothesized that Cl2 exposure resembling that in the vicinity of industrial accidents induces acute
hemolysis with
acute lung injury, reminiscent of ACS in humanized SCD mice. When exposed to Cl2 (500 ppm for 30 min), 64% of SCD mice succumbed within 6 h while none of the control mice expressing normal human
hemoglobin died (p<0.01). Surviving SCD mice had evidence of acute
hemolysis,
respiratory acidosis,
acute lung injury, and high concentrations of chlorinated palmitic and
stearic acids (p<0.05) in their plasmas and RBCs compared to controls. Treatment with a single intraperitoneal dose of human
hemopexin 30 min after Cl2 inhalation reduced mortality to around 15% (p<0.01) with reduced
hemolysis (decreased RBCs fragility (p<0.001) and returned plasma
heme to normal levels (p<0.0001)), improved oxygenation (p<0.0001) and reduced
acute lung injury scores (p<0.0001). RBCs from SCD mice had significant levels of carbonylation (which predisposes RBCs to
hemolysis) 6 h post-Cl2 exposure which were absent in RBCs of mice treated with
hemopexin. To understand the mechanisms leading to carbonylation, we incubated RBCs from SCD mice with chlorinated
lipids and identified sickling and increased
hemolysis compared to RBCs obtained from control mice and treated similarly. Our study indicates that Cl2 inhalation induces ACS in SCD mice via induction of acute
hemolysis, and that post exposure administration of
hemopexin reduces mortality and
lung injury. Our data suggest that SCD patients are vulnerable in Cl2 exposure incidents and that
hemopexin is a potential therapeutic agent.