Anti-interleukin-8 autoantibodies in patients at risk for acute respiratory distress syndrome

Kurdowska, Anna; Noble, James M.; Grant, I. S.; Robertson, Colin; Haslett, Christopher; Donnelly, Seamas C.

doi:10.1097/00003246-200210000-00024

Cited by 81 publications

(144 citation statements)

References 8 publications

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“…80,81 In one study, outcome from ARDS was better predicted by levels of IL-8:anti-IL-8 autoantibody complexes than levels of IL-8 alone, 81 even though complexing of anti-IL-8 antibody with IL-8 neutralizes its neutrophil chemotactic activity. 82 Recently the upstream regulation of transcription of proinflammatory cytokines and mediators has become a focus of pathogenetic research in ALI/ARDS. Nuclear factor kappa-B (NFkB), a transcription factor that regulates the expression of ICAM-1, IL-1b, IL-6, IL-8, and TNF-a, among others, 83,84 has been the most widely studied.…”

Section: Cytokine-mediated Inflammation and Injurymentioning

confidence: 99%

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Ware¹

2006

Semin Respir Crit Care Med

430

324

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Since the adult respiratory distress syndrome was first described substantial progress has been made in understanding the pathogenesis of this complex syndrome. This review summarizes our current understanding of the pathophysiology of what is now termed the acute respiratory distress syndrome (ARDS) and its less severe form acute lung injury (ALI), with an emphasis on cellular and molecular mechanisms of injury that may represent potential therapeutic targets. Although it is difficult to synthesize all of these abnormalities into a single, unified, pathogenetic pathway, a theme that emerges repeatedly is that of imbalance, be it between pro-and anti-inflammatory cytokines, oxidants and antioxidants, procoagulants and anticoagulants, neutrophil recruitment and activation and mechanisms of neutrophil clearance, or proteases and protease inhibitors. Future therapies aimed at restoring the overall balance of cytokines, oxidants, coagulants, and proteases may ultimately be successful where therapies that target individual cytokines or other mediators have not.

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Section: Cytokine-mediated Inflammation and Injurymentioning

confidence: 99%

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Ware¹

2006

Semin Respir Crit Care Med

430

324

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“…In several studies, neutropenia has been shown to attenuate the extent of lung damage (2, 3), highlighting the pivotal role of PMN recruitment in the early development of the disease. The human CXCR2 (and CXCR1) ligand CXCL8 is produced in the BAL of patients with ARDS and largely accounts for its chemotactic activity (9). Moreover, CXCL8 levels in the BAL have been demonstrated to affect prognosis of ARDS.…”

Section: Cells (mentioning

confidence: 99%

“…Both chemokines are functional homologs of human CXCL8 (IL-8), which has been associated with the development and outcome of ARDS (9,10). Upon activation, CXCR2 is phosphorylated, leading to receptor desensitization and internalization, intracellular removal of the ligand, and finally, degradation or re-expression of the receptor on the cell membrane (11).…”

Section: Introductionmentioning

confidence: 99%

Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung

Reutershan¹

2006

Journal of Clinical Investigation

283

294

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In models of acute lung injury, CXC chemokine receptor 2 (CXCR2) mediates migration of polymorphonuclear leukocytes (PMNs) into the lung. Since CXCR2 ligands, including CXCL1 and CXCL2/3, are chemotactic for PMNs, CXCR2 is thought to recruit PMNs by inducing chemotactic migration. In a model of PMN recruitment to the lung, aerosolized bacterial LPS inhalation induced PMN recruitment to the lung in wild-type mice, but not in littermate CXCR2 -/-mice. Surprisingly, lethally irradiated wild-type mice reconstituted with CXCR2 -/-BM still showed about 50% PMN recruitment into bronchoalveolar lavage fluid and into lung interstitium, but CXCR2 -/-mice reconstituted with CXCR2 -/-BM showed no PMN recruitment. Conversely, CXCR2 -/-mice reconstituted with wild-type BM showed a surprisingly large defect in PMN recruitment, inconsistent with a role of CXCR2 on PMNs alone. Cell culture, immunohistochemistry, flow cytometry, and real-time RT-PCR were used to show expression of CXCR2 on pulmonary endothelial and bronchial epithelial cells. The LPS-induced increase in lung microvascular permeability as measured by Evans blue extravasation required CXCR2 on nonhematopoietic cells. Our data revealed what we believe to be a previously unrecognized role of endothelial and epithelial CXCR2 in LPS-induced PMN recruitment and lung injury. IntroductionAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinical syndromes characterized by an excessive inflammatory response to both pulmonary and extrapulmonary stimuli that ultimately leads to a disruption of alveolar-capillary integrity with severe consequences for pulmonary gas exchange. Both ALI and ARDS are still associated with a high mortality, and a specific therapy is not available (1).Recruitment of neutrophils (polymorphonuclear leukocytes; PMNs) into the lung is a key event in the early development of ALI and ARDS, as previously demonstrated in neutropenic animals and humans (2, 3). PMN recruitment into the lung occurs in a cascade-like sequence of activation, sequestration in pulmonary vessels, and transendothelial (from blood to interstitium) and transepithelial (from interstitium to alveolar airspace) migration (4). Although interactions between leukocytes and endothelium have been well characterized in the systemic microcirculation, molecular requirements in the lung are not completely understood. Depending on the injury model and stimulus, adhesion molecules on leukocytes and endothelium may or may not be involved due to unique properties of the pulmonary microcirculation (5). Each migration step is regulated by distinct molecules (6), and the importance of investigating discrete steps of PMN migration in the lung has been emphasized (7).CXCR2 is a 7-transmembrane G protein-coupled receptor that is activated by CXC chemokines containing the ELR (GluLeu-Arg) motif, including murine CXCL1 (keratinocyte-derived

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“…3 The main known property of IL-8 is to induce neutrophil activation, and anti-IL-8 autoantibodies have been shown to inhibit IL-8 interaction with its specific receptors on neutrophils. 6 IL-8 also binds to heparin, 7 and there may be IL-8 receptors on platelets. [8][9][10] This study was undertaken to investigate whether antibodies to IL-8 are able to induce platelet activation in vitro and whether they are dependent on heparin.…”

Section: Introductionmentioning

confidence: 99%

Platelet activation induced by human antibodies to interleukin-8

Régnault

Maistre

Carteaux

et al. 2003

Blood

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Some cases of heparin-induced thrombocytopenia (HIT) have been reported to be associated with antibodies against interleukin-8 (IL-8), a chemokine related to platelet factor 4. We found that sera from 5 HIT patients containing immunoglobulin G (IgG) or IgM antibodies to IL-8, as evidenced using surface plasmon resonance spectroscopy, were able to trigger IL-8-dependent activation of washed platelets, leading to procoagulant activity. This activation occurred at IL-8 concentrations achievable in vivo and was facilitated by heparin (0.1 U/mL). Activation was also induced by affinity-purified anti-IL-8 IgG and involved Fc␥RIIa. In the 2 patients who could be followed up, antibodies were no longer detectable 4 months after heparin withdrawal. One additional patient with paraneoplastic recurrent thrombosis without thrombocytopenia was found to have platelet-activating anti-IL-8 IgM, but in this case heparin was inhibitory. This is another example of potentially pathogenic platelet activation by antibodies. IntroductionIn most patients with heparin-induced thrombocytopenia (HIT), antibodies bind to complexes of heparin and platelet factor 4 (PF4). If these antibodies are immunoglobulin G (IgG), they interact with Fc␥RIIa receptors and trigger platelet activation. 1,2 However, previous investigators using enzyme-linked immunosorbent assay (ELISA) have reported that a few HIT patients have antibodies specific to another, PF4-related ␣-chemokine-interleukin-8 (IL-8), alone 3,4 or in combination with antibodies to heparin-PF4 complexes. 5 These antibodies were infrequently detected in patients with heparin exposure but no thrombocytopenia and in patients with thrombocytopenia from another etiology. 3 The main known property of IL-8 is to induce neutrophil activation, and anti-IL-8 autoantibodies have been shown to inhibit IL-8 interaction with its specific receptors on neutrophils. 6 IL-8 also binds to heparin, 7 and there may be IL-8 receptors on platelets. [8][9][10] This study was undertaken to investigate whether antibodies to IL-8 are able to induce platelet activation in vitro and whether they are dependent on heparin. Study designSera were obtained from 5 selected patients (P1-P5) who fulfilled the diagnostic criteria for HIT 1,11 (suggestive temporal pattern of platelet counts in relation to heparin therapy and evidence for heparin-dependent platelet-activating antibodies) but without IgG to heparin-PF4 complexes. 3 Patient 6 had typical HIT with IgG to heparin-PF4 only. One additional patient (P7), who had experienced fatal recurrent paraneoplastic thromboses while on heparin therapy without thrombocytopenia, 12 was also studied. Small volumes of blood were collected from samples required for routine patient management and were withdrawn after heparin therapy was stopped; heparin was no longer detectable with anti-Xa assay. ELISA (Asserachrom HPIA; Diagnostica Stago, Asnières, France) was used to detect antibodies to heparin-PF4. 13 IgG was purified by affinity chromatography on protein G-Sepharose (Pharmacia Bi...

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Anti-interleukin-8 autoantibodies in patients at risk for acute respiratory distress syndrome

Abstract: Bronchoalveolar lavage fluid concentration of anti-interleukin-8:interleukin-8 complexes may serve as a marker of disease progression in patients at risk for acute respiratory distress syndrome.

Cited by 81 publications

References 8 publications

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung

Platelet activation induced by human antibodies to interleukin-8

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