Pulmonary Stromal-Derived Factor-1 Expression and Effect on Neutrophil Recruitment during Acute Lung Injury

Abstract

The severe and protracted inflammation that characterizes acute lung injury (ALI) is driven by the ongoing recruitment of neutrophils to the lung. Although much of the cytokine signaling responsible for the initial phase of ALI has been elaborated, relatively little is known about the mechanisms governing the recruitment of neutrophils from the bone marrow to the lung in the later period of this disease. Given its previously described chemoattractant effects on marrow neutrophils, we investigated whether stromal-derived factor-1 (SDF-1) (CXCL12) might participate in this later phase of recruitment. Using immunohistochemistry to examine both banked human lung specimens from patients with ALI and lungs from mice with LPS-induced pneumonitis, we found that pulmonary SDF-1 expression increases during ALI. We further determined that both lung SDF-1 protein expression and mRNA expression rise in a delayed but sustained pattern in this mouse model and that the major source of the increase in expression appears to be the lung epithelium. Lastly, we found that expression of the SDF-1 receptor CXCR4 rises in a similar temporal pattern on neutrophils in both the blood and airspace of LPS-injured mice and that Ab-mediated SDF-1 blockade significantly attenuates late but not early pulmonary neutrophilia in this model. These results implicate SDF-1 in neutrophil recruitment to the lung in the later period of acute lung injury and suggest a novel role for this cytokine in coordinating the transition from the inflammatory response to the initiation of tissue repair.

The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury

“…Previous reports by our group and other investigators have shown that CXCL12 levels are upregulated in injured lungs and that in vivo administration of anti-CXCL12 blocking antibodies suppresses airspace neutrophilia in the lungs at the later stages of LPS-induced lung injury, [17][18][19] suggesting that the increase of surface CXCR4 expression on lung extravasated neutrophils cooperates with the increase of CXCL12 in the lungs to facilitate the accumulation of neutrophils. To confirm the in vivo role of the CXCL12/CXCR4 signaling system in the pathogenesis of acute lung injury, we administrated a specific CXCR4 antagonist to block the activation of CXCR4.…”

“…Because CXCL12 is also upregulated in the injured lungs, [17][18][19] these findings suggest that the increase in surface CXCR4 expression levels on extravasated neutrophils acts together with the increase of CXCL12 in the lungs to promote neutrophil migration and/or retention within the airspace.…”

“…14,16 In addition to the evidence supporting the role of CXCL12/CXCR4 in modulating neutrophil homeostasis, we and other investigators previously reported that both CXCL12 levels in the injured lungs and surface CXCR4 protein on accumulated neutrophils were increased; furthermore, the in vivo administration of an anti-CXCL12 blocking antibody suppressed airspace neutrophilia in the lungs in the later stages of lipopolysaccharide (LPS)-induced lung injury. [17][18][19] These findings suggested that this chemokine participated in the accumulation of neutrophils in the injured tissue, particularly in the later stages of inflammation. However, the mechanisms underlying the increase in surface CXCR4 expression on neutrophils during LPS-induced lung injury and the CXCL12-promoted accumulation of neutrophils remain unclear.…”

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

“…Petty et al identified stromal cell-derived factor (SDF)-1 as the major chemokine important in sustained neutrophilic responses in the endotoxin-treated murine lung [70]. They also demonstrated the progressive upregulation of its receptor CXCR4 on neutrophils.…”

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

“…CXCL12/CXCR4 not only regulates the development of T and B lymphocytes but also contributes to the survival of mature lymphocytes and in the generation of memory T cells (Klein RS and Rubin JB, 2004). Recent studies indicate that CXCL12/CXCR4 enhances the inflammatory infiltration of neutrophils or lymphocytes in diverse models and settings involving acute inflammation or fulminant infection (Wald O et al, 2004;Ding Z et al, 2006;Petty JM et al, 2007). CXCL12 is an important regulator for homing of hematopoietic progenitor cells (HPCs) to the bone marrow (BM) microenvironment (Lapidot T et al, 2005).…”