Evidence for chemokine synergy during neutrophil migration in ARDS

Abstract

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by pulmonary oedema, respiratory failure and severe inflammation. ARDS is further characterised by the recruitment of neutrophils into the lung interstitium and alveolar space.ObjectivesThe factors that regulate neutrophil infiltration into the inflamed lung and our understanding of the pathomechanisms in ARDS remain incomplete. This study aimed at determining the role of the chemokine (C-C motif) ligand (CCL)2 and CCL7 in ARDS.MethodsCCL2 and CCL7 protein levels were measured in bronchoalveolar lavage (BAL) fluid obtained from lipopolysaccharide(LPS)-challenged human volunteers and two separate cohorts of patients with ARDS. Neutrophil chemotaxis to ARDS BAL fluid was evaluated and the contribution of each was assessed and compared with chemokine (C-X-C motif) ligand 8 (CXCL8). Chemokine receptor expression on neutrophils from blood or BAL fluid of patients with ARDS was analysed by flow cytometry.ResultsCCL2 and CCL7 were significantly elevated in BAL fluid recovered from LPS-challenged volunteers and patients with ARDS. BAL fluid from patients with ARDS was highly chemotactic for human neutrophils and neutralising either CCL2 or CCL7 attenuated the neutrophil chemotactic response. Moreover, CCL2 and CCL7 synergised with CXCL8 to promote neutrophil migration. Furthermore, neutrophils isolated from the blood or BAL fluid differentially regulated the cell surface expression of chemokine (C-X-C motif) receptor 1 and C-C chemokine receptor type 2 during ARDS.ConclusionThis study highlights important inflammatory chemokines involved in regulating neutrophil migration, which may have potential value as therapeutic targets for the treatment of ARDS.

CXCL10/IP-10 Neutralization Can Ameliorate Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Rats

“…Because neutrophil-mediated lung injury plays a pivotal role in ARDS, chemokines that may contribute to neutrophil chemotaxis were further studied. Some chemokines including CXCL8, C-C motif chemokine ligand 2 (CCL2), and CCL7 are known to enhance neutrophil activation and migration [10, 39]. Besides chemokines, peripheral blood monocytes, along with alveolar macrophages may influence neutrophil migration and their depletion prior to LPS exposure can diminish neutrophil trafficking.…”

“…In addition, the excessive activation and recruitment of neutrophils into inflamed lungs exacerbates the pathogenesis of ARDS and may indicate a poor clinical outcome [8, 9]. Neutrophils migration to the lung is mediated by various factors, among which chemokines and cell adhesion molecules are considered the most important [10]. The C-X-C motif chemokine10(CXCL10), also known as interferon-γ inducible protein 10 (IP-10), is a chemokine that modulates innate and adaptive immune responses by recruiting inflammatory cells (i.e., neutrophils, T lymphocytes and NK cells) to the sites of inflammation [11].…”

What drives neutrophils to the alveoli in ARDS?

“…In Thorax, Williams et al 19 tested their experimental findings in patients, asking whether CCL2 and CCL7 are similarly important in neutrophil recruitment in ARDS. Both CCL2 and CCL7 were elevated in the bronchoalveolar lavage (BAL) fluid of patients with ARDS and the neutrophil chemotactic activity of BAL fluid was as much attributable to either CCL2 or CCL7 as to CXCL8.…”

Dapsone as treatment adjunct in ARDS

“…IL-8 is elevated in human bronchoalveolar lavage fluid of ARDS where higher lavage concentrations correlate with higher diffuse alveolar damage and mortality. [20][21][22][23] Also higher lavage fluid IL-8 correlated with higher neutrophil infiltration. 22 High circulating IL-8 characteristic of ARDS does not act alone in attracting neutrophils to the lung.…”

“…IL-8 acts as part of a suite of chemokines, albeit having a central, pivotal role. 23,24 Dapsone has a long history of use in treating the neutrophilic dermatoses, rheumatoid arthritis, and use in other non-antibiotic roles. 25,26 This use led to the discovery that dapsone ameliorates these dermatoses primarily by inhibiting neutrophil migration along an IL-8 gradient.…”