Haptoglobin Protects Against Increased Chlorine Inhalation Vulnerability in Sickle Cell Trait Mice
Ammar Saadoon Alishlash, Changchun Ren, Zhihong Yu, Brian A Halloran, Shubham Dubey, Junaid Khan, Malgorzata Kasztan, Vinitha Uppalapati, Subhashini Bolisetty, Brianna Pittman, Sura Ahmed, James Mobley, Tamas Jilling, Sadis MatalonAbstract
Rationale
Sickle cell trait (SCT), carried by millions worldwide, is generally considered benign. However, SCT is increasingly linked to life‑threatening complications under environmental stress.
Objectives
We tested whether sickle cell trait confers heightened vulnerability to oxidant inhalation injury and whether post-exposure haptoglobin mitigates injury.
Methods
Using humanized SCT (AS) and control hemoglobin (AA) mice carrying human hemoglobin knock‑in genes, we examined physiologic, biochemical, histologic, mitochondrial, and proteomic responses to chlorine (Cl₂) inhalation at concentrations encountered near chemical accidents. Pulmonary and kidney injury were assessed 24 h post‑exposure.
Measurements and Main Results
Compared with AA controls, SCT mice exhibited markedly increased mortality, severe acute lung and kidney injury, hypoxemia, and exaggerated hemolysis/rhabdomyolysis following Cl2 exposure. Global lung proteomics revealed widespread remodeling, with modifications to lung proteins. Systems biology analysis revealed that neutrophil degranulation, acute‑phase, and oxidative/mitochondrial injury pathways were uniquely intensified in SCT. To test whether scavenging extracellular hemoglobin mitigates injury, mice received haptoglobin 30 min after Cl2 exposure. Post‑exposure haptoglobin significantly improved survival, oxygenation, renal function, and epithelial barrier integrity, while reversing key inflammatory and mitochondrial injury signatures and restoring proteomic architecture to near-baseline levels.
Conclusions
Our data showed that Cl2 inhalation triggers hemolysis-driven multiorgan injury in SCT, establishing SCT as a previously unrecognized high-risk phenotype for toxic environmental exposures. Haptoglobin administered after exposure provides robust protection across physiologic, molecular, and mitochondrial endpoints, supporting hemoglobin scavenging as a practical, rapidly deployable countermeasure for chemical inhalational injury in individuals with SCT.