Dose-related protection from nickel-induced lung injury in transgenic mice expressing human transforming growth factor-alpha.
To determine the role of transforming growth factor-alpha (TGF-alpha) in protecting the lung from aerosolized nickel injury, transgenic mouse lines expressing human TGF-alpha in the pulmonary epithelium, under control of the human surfactant protein-C gene promoter, were tested. Higher expressing TGF-alpha transgenic mouse lines, expressing distinct levels of TGF-alpha, survived longer than nontransgenic control mice. Increased survival correlated with levels of TGF-alpha expression in the lung. After 72 h of nickel exposure (70 microg Ni/m3), transgenic lines with intermediate levels of the TGF-alpha expression demonstrated attenuation of lung injury. The highest expressing line (line 28) demonstrated reduced lung inflammation and edema, reduced lung wet-to-dry weight ratios, decreased bronchoalveolar lavage (BAL) protein and neutrophils, reduced interleukin (IL)-1beta, interleukin-6, and macrophage inflammatory protein-2, and maintained surfactant protein-B (SP-B) levels compared with nontransgenic controls. In the TGF-alpha transgenic mouse model, TGF-alpha protects against nickel-induced acute lung injury, at least in part, by attenuating the inflammatory response, reducing pulmonary edema, and preserving levels of SP-B.
Hardie
William D
WD
Division of Pulmonary Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. bill.hardie@chmcc.org
Prows
Daniel R
DR
Piljan-Gentle
Alyssa
A
Dunlavy
Michelle R
MR
Wesselkamper
Scott C
SC
Leikauf
George D
GD
Korfhagen
Thomas R
TR
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism; D009504:Neutrophils; D009532:Nickel / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D011510:Proteolipids / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D015996:Survival Rate; D016211:Transforming Growth Factor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D009363:Neoplasm Proteins; C418133:PARP9 protein, human; D011506:Proteins; D011510:Proteolipids; D011663:Pulmonary Surfactants; D016211:Transforming Growth Factor alpha; D009532:Nickel; D011065:Poly(ADP-ribose) Polymerases