Exacerbation by granulocyte colony-stimulating factor of prior acute lung injury: implication of neutrophils.

Abstract

OBJECTIVE:

Granulocyte colony-stimulating factor is widely prescribed to hasten recovery from cancer chemotherapy-induced neutropenia and has been reported to induce pulmonary toxicity. However, circumstances and mechanisms of this toxicity remain poorly known.

DESIGN:

To reproduce a routine situation in cancer patients receiving chemotherapy, we investigated the mechanisms underlying granulocyte colony-stimulating factor-induced exacerbation of alpha-naphthylthiourea-related pulmonary edema.

SETTING:

Laboratory research unit.

SUBJECTS:

Male specific-pathogen-free Sprague-Dawley rats.

INTERVENTIONS:

The effects of granulocyte colony-stimulating factor given alone or after alpha-naphthylthiourea used to induce acute lung injury were investigated.

MEASUREMENTS AND MAIN RESULTS:

Lung injury was assessed based on neutrophil sequestration (myeloperoxidase activity in lung tissue) and influx into alveolar spaces (bronchoalveolar lavage fluid cell quantification) and on edema formation (wet/dry lung weight ratio) and alveolar protein concentration into bronchoalveolar lavage fluid. Tumor necrosis factor-alpha and interleukin-1beta were measured in serum, lung homogenates, and isolated alveolar macrophage supernatants. In control rats, granulocyte colony-stimulating factor (25 microg/kg) significantly elevated circulating neutrophil counts without producing alveolar recruitment or pulmonary edema. alpha-Naphthylthiourea significantly increased the wet/dry lung weight ratio (4.68 +/- 0.04 vs. 4.38 +/- 0.07 in controls, p=.04) and induced alveolar protein leakage. Adding granulocyte colony-stimulating factor to alpha-naphthylthiourea exacerbated pulmonary edema, causing neutrophil sequestration in pulmonary vessels, significantly increasing lung myeloperoxidase activity (12.7 +/- 2.0 mOD/min/g vs. 1.1 +/- 0.4 mOD/min/g with alpha-naphthylthiourea alone; p<.0001), and increasing proinflammatory cytokine secretion. alpha-Naphthylthiourea-related pulmonary edema was not exacerbated by granulocyte colony-stimulating factor during cyclophosphamide-induced neutropenia or after lidocaine, which antagonizes neutrophil adhesion to endothelial cells. Tumor necrosis factor-alpha and interleukin-1beta concentrations in alveolar macrophage supernatants and lung homogenates were significantly higher with alpha-naphthylthiourea + granulocyte colony-stimulating factor than with either agent alone, and anti-tumor necrosis factor-alpha antibodies abolished granulocyte colony-stimulating factor-related exacerbation of alpha-naphthylthiourea-induced pulmonary edema. In rats with cyclophosphamide-induced neutropenia, tumor necrosis factor-alpha concentrations in alveolar macrophage supernatants and lung homogenates were significantly decreased compared with rats without neutropenia.

CONCLUSION:

Granulocyte colony-stimulating factor-related pulmonary toxicity may involve migration of neutrophils to vascular spaces, adhesion of neutrophils to previously injured endothelial cells, and potentiation of proinflammatory cytokine expression.

• Authors: Elie Azoulay, Habiba Attalah, Kun Yang, Hélène Jouault, Benoît Schlemmer, Christian Brun-Buisson, Laurent Brochard, Alain Harf, Christophe Delclaux
• Journal: Critical care medicine (Crit Care Med) Vol. 30 Issue 9 Pg. 2115-22 (Sep 2002) ISSN: 0090-3493 [Print] United States
• PMID: 12352050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Cytokines
• Rodenticides
• Granulocyte Colony-Stimulating Factor
• Cyclophosphamide
• Peroxidase
• Thiourea
• alpha-naphthyl thiourea

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Cyclophosphamide (therapeutic use)
• Cytokines (blood, metabolism)
• Drug Interactions
• Granulocyte Colony-Stimulating Factor (adverse effects)
• Lung (drug effects, enzymology, metabolism)
• Male
• Neutropenia (chemically induced)
• Neutrophils (drug effects)
• Peroxidase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Respiratory Distress Syndrome (chemically induced, prevention & control)
• Rodenticides (toxicity)
• Thiourea (analogs & derivatives, toxicity)