Thorax Online First, published on October 18, 2016 as 10.1136/thoraxjnl-2016-209170 Editorial 13 24 are elevated in human ARDS. Thorax: first published as 10.1136/thoraxjnl-2016-209170 on 18 October 2016. Downloaded from What drives neutrophils to the alveoli However, the new evidence that the neutro- phil chemotactic activity in BAL fluid from in ARDS? patients with ARDS is highly attributable to CCL2 and CCL7 and that CCL2/7 potenti- 1,2 3,4 Rachel L Zemans, Michael A Matthay ates the chemotactic activity of CXCL8 is novel and important. Moreover, given that the neutrophils used in the chemotaxis Neutrophil influx into the extravascular prototypical neutrophil chemokines.12 assays were isolated from the blood of compartments of the lungs is a defining CXC chemokines are elevated in patients healthy volunteers, which likely express less characteristic of the Acute Respiratory with ARDS13 and animal models of lung CCR2thanthoseactivelymigratinginto Distress Syndrome (ARDS).1 During injury,712and CXCL8 levels are predictive the lungs during ARDS, the role of CCL2 ARDS, circulating neutrophils become of disease development,14 severity15 and andCCL7inneutrophilchemotaxisin primed, resulting in reduced deformability mortality.16 However, although CXC che- ARDS may even be underestimated. and retention within the pulmonary capil- mokines are responsible for much of the These studies raise several mechanistic lary bed23followed by migration across neutrophil recruitment to the lungs during questions. First, the extent to which CCL2/ the endothelium, through the interstitium lung injury, blockade of CXCL8 or CXCL1/ 7 are directly chemotactic for neutrophils and across the epithelium into the air- 2 prevents some but not all neutrophil is unclear, as the degree of neutrophil spaces.4 As neutrophils migrate, they may recruitment.712Additional CXC chemo- chemotaxis induced by recombinant CCL2 become activated to phagocytose invading kines such as CXCL5 (LIX/ENA-78), or CCL7 was small and did not reach statis- pathogens and release oxidants, proteases CXCL12 (SDF-1) and CXCL15 (lungkine), tical significance, even with concentrations and neutrophil extracellular traps, all of as well as other mediators such as LTB4 and of recombinant chemokines much higher which play a role in killing pathogens. C5a, also are neutrophil chemoattractants.8 than those detected in the BAL fluid of Although neutrophils may migrate into Chambers et al have previously pub- patients with ARDS. Still, reasonable con- the airspaces without inducing an increase lished elegant animal studies demonstra- centrations of CCL2/7 do enhance the in protein permeability under certain con- ting that the CC chemokines CCL2 chemotactic potency of CXCL8. While the ditions,5 in ARDS neutrophils and their (MCP-1) and CCL7 (MCP-3), classically authors speculate that enhanced receptor toxic mediators can cause tissue injury, chemotactic for monocytes,11 contribute occupancy may contribute to this synergis- including an increase in lung epithelial to neutrophil recruitment in acute lung tic effect, future studies should explore the – and endothelial permeability6 9 which injury. After challenge with lipopolysac- mechanism underlying this effect as well as leads to the influx of protein-rich alveolar charide (LPS) or live bacteria, CCL2 and whether CCL2/7 also acts in synergy with oedema and arterial hypoxaemia.10 In CCL7 were rapidly upregulated in the other CXC (or CC) chemokines. In add- fact, mortality from ARDS correlates with lungs, the CC chemokine receptors CCR1 ition, the cellular sources of CCL2 and the extent of neutrophilia in the lung.1 and CCR2 were expressed on neutrophils, CCL7 and the mechanisms that induce Treatment for ARDS is mainly supportive, and blockade of CCL2 and/or CCL7 atte- their synthesis are not completely consisting of low tidal volume ventilation nuated neutrophil recruitment.17 18 understood. Reports suggest the alveolar http://thorax.bmj.com/ and fluid restriction, approaches which In Thorax, Williams et al19 tested their and bronchial epithelium as likely have substantially improved outcomes. experimental findings in patients, asking sources,17 23 25 and expression appears to However, to further improve outcomes, whether CCL2 and CCL7 are similarly be regulated by proteinase-activated recep- specific therapies to limit inflammatory important in neutrophil recruitment in tors.17 18 In addition, while the authors lung injury while preserving host defense ARDS. Both CCL2 and CCL7 were ele- have demonstrated that CCL2/7 are dir- are needed. Therefore, it is critical that vated in the bronchoalveolar lavage (BAL) ectly chemotactic for neutrophils, there we understand the mechanisms regulating fluid of patients with ARDS and the neu- may be additional mechanisms through fl neutrophil recruitment, priming, activa- trophil chemotactic activity of BAL uid which CCL2/7 induce neutrophil recruit- on October 3, 2021 by guest. Protected copyright. tion and effector functions. was as much attributable to either CCL2 ment, such as via activation of resident Leucocyte chemokines are classified into or CCL7 as to CXCL8. Although CCL2 alveolar macrophages or epithelial cells to several families based on the position of and CCL7 were weaker neutrophil che- secrete CXC chemokines or by inducing cysteine (C) residues: CXC, CC, C and moattractants than CXCL8 when chemo- monocyte recruitment, which in turn may CX3C.11 Neutrophil migration has classic- taxis towards recombinant chemokines facilitate neutrophil recruitment.26 In addi- ally been thought to be driven by the CXC was tested, CCL2 and CCL7 each signifi- tion, investigation of the extent to which chemokines, with CXCL8 (interleukin 8) in cantly enhanced neutrophil chemotaxis to these CC chemokines induce chemotaxis humans and its orthologs CXCL1 (KC) and CXCL8, suggesting that the effect is syn- and prime and activate neutrophils and CXCL2 (MIP2) in mice being the ergistic. Finally, their studies demonstrated prolong neutrophil life span, as CXCL8 that the CXC chemokine receptor can, is warranted. Along these lines, 1 CXCR1 was downregulated while the CC additional studies should be done to deter- Department of Medicine, National Jewish Health, chemokine receptor CCR2 was upregu- Denver, Colorado, USA; 2Department of Medicine, mine whether blockade of these University of Colorado Denver, Aurora, Colorado, USA; lated as neutrophils migrated from the chemokines also mitigates lung injury (per- 3The Cardiovascular Research Institute, University of bloodstream into the airspaces (figure 1). meability) in human ARDS models, as is California San Francisco, San Francisco, California, This study was rigorously performed, 7 4 the case with CXCL8 blockade. Finally, USA; Departments of Medicine and Anesthesiology, leading to well justified conclusions. The the effect of CCL2/7 inhibition, with asso- University of California, San Francisco, California, USA findings are consistent with prior literature ciated blockade of neutrophil influx, on Correspondence to Professor Michael A Matthay, demonstrating that CCL2 and CCL7 can the ability of the lungs to clear bacteria Departments of Medicine and Anesthesiology, 505 20 21 Parnassus Avenue, M-917, San Francisco, CA 94143- function as neutrophil chemoattractants, should be tested in ARDS models of live 22 23 0624, USA; [email protected] including in models of lung injury, and bacterial infection. Zemans RL, Matthay MA. Thorax Month 2016 Vol 0 No 0 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Editorial Thorax: first published as 10.1136/thoraxjnl-2016-209170 on 18 October 2016. Downloaded from Figure 1 Neutrophil influx in ARDS. In patients with acute lung injury from ARDS, resident lung cells such as macrophages secrete chemokines that induce neutrophils or polymorphonuclear cells (PMN) to migrate from the bloodstream into the airspaces. Classically, neutrophil migration has been thought to be driven by CXC chemokines, with CXCL8 being the protypical neutrophil chemokine, inducing migration by acting on its receptors, mainly CXCR1 in humans. Chambers et al have demonstrated that two members of the CC family of chemokines, CCL2 and CCL7, are upregulated in the lungs of patients with ARDS. Their receptor, CCR2, is upregulated on neutrophils as they migrate from the vasculature into the airspaces, while CXCR1 is downregulated. Moreover, these CC chemokines act in synergy with CXCL8 to induce neutrophil influx. As neutrophils migrate into the lungs, they become activated, releasing toxic mediators such as reactive oxygen species (ROS), proteases and neutrophil extracellular traps (NETs), which function to kill invading pathogens but also may cause epithelial and endothelial injury, leading to the development of protein-rich alveolar oedema. Figure prepared by Diana Lim. http://thorax.bmj.com/ The holy grail of ARDS therapy would likely to be a critical determinant of the activity of others could theoretically miti- be to limit neutrophil recruitment and specific chemokine-receptor pathways gate neutrophil-dependent tissue damage priming/activation while preserving host involved. In mice, both CCL2 and CCL7 without impairing host defense. However, defence. However, neutrophil function is were important neutrophil chemokines in because the mediators that induce neutro- complex, requiring migration, priming the LPS model, while in the phil chemotaxis and activation are Streptococcus pneumoniae and activation, each potentially