Association of Endogenous G-CSF with Anti-Inflammatory Mediators in Patients with Acute Respiratory Distress Syndrome

Abstract

Upregulation of the anti-inflammatory mediators, soluble tumor necrosis factor-alpha receptors I and II (sTNFRI/RII) and interleukin-1 receptor antagonist (IL-1RA), by granulocyte colony-stimulating factor (G-CSF) may contribute to the pathophysiology of lung injury. We determined the relation of endogenous G-CSF to proinflammatory and anti-inflammatory mediators in bronchoalveolar lavage fluid (BALF) and serum of patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Nineteen patients with ARDS and 10 with ALI were included in this prospective investigation. BAL was performed within 12 h and 24 h after onset of lung injury. Concentrations of G-CSF, TNF-alpha, IL-6, sTNFRI and sTNFRII, IL-1RA and IL-10 in BALF as well as in serum were determined by ELISA. G-CSF was associated with alveolar neutrophilia. Results in patients with ARDS and ALI exhibited significant positive correlations in BALF of G-CSF levels with that of IL-6, sTNFRII, and IL-1RA and of G-CSF levels in serum with that of serum IL-6, IL-1RA, and IL-10. Given the potential of G-CSF to directly induce anti-inflammatory cytokines in vitro, significant associations of endogenous G-CSF levels with these mediators early in the development of severe lung injury suggest an endogenous anti-inflammatory role of G-CSF in vivo.

Genetic and Pharmacologic Evidence Links Oxidative Stress to Ventilator-induced Lung Injury in Mice

“…We also found enhanced levels of GCSF, which is important for neutrophil accumulation and activation in the lungs (43). High levels of GCSF correlate with ARDS in humans (44)(45)(46), and administration of GCSF induces ALI in animals (43,47). We also found elevated levels of IL-6 in the lungs of Nrf2 2/2 mice compared with Nrf2 1/1 mice in response to MV, suggesting that this cytokine may play a role in causing VILI.…”

Respiratory status deterioration during G-CSF-induced neutropenia recovery

“…27,28 G-CSF upregulates the production of cytokines that increase alveolar permeability or neutrophil influx, such as tumor necrosis factor (TNF) a, interleukin (IL) 1b, and IL-8. 29,30 In vitro studies also found enhanced secretion of proinflammatory cytokines by isolated alveolar macrophages obtained during neutropenia recovery from rats that received G-CSF, compared with rats that did not receive G-CSF, providing a possible explanation for lung injury exacerbation during G-CSF-induced neutropenia recovery. 18 Our study has some limitations, however.…”

Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

“…The role of IL-1Ra in lung injury is not well characterized, although a murine knockout study showed that IL-1Ra may have an antiinflammatory effect in, and promote resolution after, LPS-induced injury (36). Increased BAL IL-1Ra has been shown in patients with ARDS, and is proposed as a potential endogenous antiinflammatory mediator to limit damage in acute lung injury (ALI) (37). Mesenchymal stem cells, which reduce lung injury in animal models, are associated with increased pulmonary IL-1Ra concentrations (38), whereas aerosolized Anankinra, recombinant human IL-1Ra, reduced pulmonary arterial pressure and gene expression of IL-8 and IL-1b in a porcine model of lung injury, suggesting a reparative role for exogenous IL-1Ra (39).…”