Monocyte dependent microvascular lung injury and endoplasmic reticulum stress in SLE-associated alveolar hemorrhage and pulmonary vasculitis 2652

Abstract Description Human COPA mutations affecting retrograde Golgi-to-endoplasmic reticulum (ER) protein transport cause diffuse alveolar hemorrhage (DAH) and ER stress (“COPA syndrome”). SLE patients also can develop DAH. C57BL/6 (B6) mice with pristane-induced lupus develop severe DAH indistinguishable from human DAH, whereas BALB/c mice are resistant. We found the pristane induced DAH depends on monocytes/macrophages, but not neutrophils. Copa mRNA and protein expression were impaired in B6 mice with pristane-induced DAH, but not in pristane-treated BALB/c mice. An ER stress response was seen in lung from pristane-treated B6, but not BALB/c, mice. Resistance of BALB/c mice to DAH was overcome by treating with low-dose thapsigargin plus pristane. CB6F1 mice did not develop DAH or ER stress, suggesting that susceptibility was recessive. Increased pulmonary expression of von Willebrand factor (Vwf), a marker of endothelial injury, and the chemokine Ccl2 in DAH suggested that pristane promotes lung microvascular injury and monocyte recruitment. Lung endothelial cells and infiltrating bone marrow-derived cells from pristane-treated B6 mice expressed BiP and showed evidence of apoptosis. COPA expression also was low in SLE patients with lung involvement. Pristane-induced DAH may be initiated by endothelial injury, resulting in ER stress, apoptosis of lung endothelial cells, and recruitment of myeloid cells that propagate lung injury. The pathogenesis of DAH in SLE and COPA syndrome may overlap. Funding Sources National Institutes of Health (NIAMS) grant number R01-AR44731 Topic Categories Basic Autoimmunity (BA)