Cigarette Smoke Exposure Worsens Endotoxin-Induced Lung Injury and Pulmonary Edema in Mice.
BACKGROUND
Cigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar-epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice.


METHODS
Adult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA.


RESULTS
In CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T-cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability.


CONCLUSIONS
These results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury.


CONCLUSIONS
Our results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for evaluating the acute pulmonary toxicity of existing and/or novel tobacco products and identifying biomarkers of tobacco-related lung injury.
Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.
Jeffrey E
JE
Gotts
Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.
Jason
J
Abbott
Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.
Xiaohui
X
Fang
Department of Pathology, University of California, San Francisco, CA.
Haru
H
Yanagisawa
Department of Pathology, University of California, San Francisco, CA.
Naoki
N
Takasaka
Department of Pathology, University of California, San Francisco, CA.
Stephen L
SL
Nishimura
Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.
Carolyn S
CS
Calfee
Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.
Michael A
MA
Matthay
D000818:Animals; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D055370:Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D011654:Pulmonary Edema / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D012128:Respiratory Distress Syndrome; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D008070:Lipopolysaccharides; D014028:Tobacco Smoke Pollution