Improving the diagnosis and outcome of diffuse alveolar hemorrhage in systemic lupus erythematosus

University Of Florida, Gainesville FL

Investigators

Abstract

PROJECT SUMMARY The variable clinical manifestations of SLE patients are largely unexplained. Although severe diffuse alveolar hemorrhage (DAH) with pulmonary capillaritis is unusual in lupus, more than half of patients with this complication die and focal lung hemorrhage occurs in 30-66% of patients. Using a mouse model (pristane-induced lupus) developed in our laboratory, we will ask why C57BL/6 (B6) mice are susceptible to pristane-induced DAH/vasculitis whereas BALB/c and DBA/2 mice are resistant. DAH is initiated by lung endothelial cell (EC) injury followed by recruitment of bone marrow-derived monocytes to the lung. We found that dysregulation of the extrinsic coagulation pathway also is involved and that lung disease is abolished by early treatment with MEK1/2 or ERK1/2 inhibitors. The overall hypothesis is that genetically- determined lung microvascular EC injury evolves into DAH because of monocyte infiltration into the lung and abnormal regulation of the extrinsic coagulation pathway. Aim 1 addresses susceptibility to DAH. We will ask whether EC injury and bleeding are lung-specific and investigate gene expression patterns associated with DAH by single-cell RNA-sequencing. Genes conferring susceptibility/resistance to EC injury and bleeding be mapped in recombinant inbred BXD (B6 X D2) mice. Aim 2 examines the MEK1/2-ERK1/2 pathway in pristane-induced DAH. We will define the sequence of events leading to DAH and develop blood-based diagnostic tests for the diagnosis of incipient DAH prior to the onset of bleeding. This is important, because the disease process is irreversible once hemorrhage begins. We will look for tests that distinguish early DAH (pre-bleeding) from other forms of lung injury, such as sepsis with acute respiratory distress syndrome. Aim 3 translates what is learned in mice to human DAH. We hypothesize that the disease process is similar except that the initial EC injury is caused by respiratory viral infections rather than pristane. We will ask if a predisposition to lung EC injury determines susceptibility, as in mice, and whether diagnostic approaches developed in the mouse model are relevant to human DAH. Lung EC injury will be examined in SLE patients with influenza or COVID infection and the role of mild bleeding disorders will be explored. The ability to diagnose incipient DAH (pre- bleeding) may permit future therapeutic trials using FDA-approved MEK1/2 inhibitors, such as trametinib, which are highly effective in pristane-induced DAH.