Caveolin‐1 Is a Central Mediator of Acute Lung Injury in an Animal Model of Sickle Cell Disease

Abstract

Acute chest syndrome in sickle cell disease (SCD) carries high morbidity and mortality, with up to 15% of patients requiring invasive mechanical ventilation. However, the rates and mechanisms of ventilator-induced lung injury (VILI) in SCD remain poorly understood. We hypothesized individuals with SCD are protected from VILI in a caveolin-1 (Cav-1) dependent manner. SCD mice and control littermates underwent either spontaneous tidal breathing or high tidal volume mechanical ventilation for 4 h (VILI model), or received intratracheal Escherichia coli-derived lipopolysaccharide (LPS) or sterile phosphate-buffered saline and recovered for 16 h (LPS model). Bronchoalveolar lavage (BAL) samples were analyzed for inflammatory cytokine profiles and lung tissues were used for histology and Western blot. SCD mice were protected from VILI but were more susceptible to LPS-induced lung injury, as evidenced by higher BAL fluid total protein concentrations, polymorphonuclear cell infiltration and total cell count. Inflammatory cytokine profiles differed significantly in BAL fluid: IL-6, KC and MIP-2 levels were attenuated in the SCD-VILI model, while TNF-α levels were significantly increased after LPS exposure. Cav-1 expression was reduced at baseline in SCD mice and further decreased after exposure to VILI when compared to control animals. Phosphorylated Cav-1 expression increased, leading to depletion of total Cav-1 in the SCD-VILI model. These data suggest SCD mice are protected from VILI, but not LPS-induced lung injury. These differences appear to be mediated by distinct inflammatory cytokine profiles and expression of Cav-1. Further studies are needed to explore differences in lung injury patterns in patients with SCD.