Exacerbation of bleomycin-induced injury and fibrosis by pneumonectomy in the residual lung of mice.
BACKGROUND
Lung resection after induction chemotherapy and/or radiotherapy for down-staging of locally advanced lung cancer can be complicated with lethal interstitial pneumonia. We studied the effects of pneumonectomy on bleomycin-induced lung injury and fibrosis in mice.


METHODS
The mice underwent left pneumonectomy or a sham thoracotomy after intratracheal administration of saline or bleomycin. Lung permeability index, wet-to-dry weight ratio, histological changes, collagen contents, and concentrations of inflammatory mediators and cell counts in broncho-alveolar lavage (BAL) fluid were assessed in the residual right lung 7 d after surgery.


RESULTS
The index of capillary permeability, lung water content, and inflammatory cell counts in BAL fluid were significantly increased by pneumonectomy. These measurements were highest in the mice with both pneumonectomy and intratracheal administration of bleomycin. Similarly, fibrotic change in lung pathology, as well as an increase in lung collagen content, was most prominent in the mice exposed to both interventions. The BAL fluid concentrations of interleukin-1beta, interleukin-6, RANTES, and high mobility group box 1 were significantly increased by pneumonectomy and enhanced by the additional administration of bleomycin.


CONCLUSIONS
The results of this study indicate that pneumonectomy alone causes noncritical lung injury, which amplifies the inflammatory response to bleomycin and promotes lung fibrosis. Several inflammatory mediators appear to be involved in the exacerbation of bleomycin-induced lung injury and fibrosis.
Kakizaki
Toru
T
Department of Surgery, National Hospital Organization Kanagawa Hospital, Kanagawa, Japan.
Kohno
Mitsutomo
M
Watanabe
Masazumi
M
Tajima
Atsushi
A
Izumi
Yotaro
Y
Miyasho
Taku
T
Tasaka
Sadatomo
S
Fukunaga
Koichi
K
Maruyama
Ikuro
I
Ishizaka
Akitoshi
A
Kobayashi
Koichi
K
D055371:Acute Lung Injury / Q000139:chemically induced / Q000473:pathology* / Q000601:surgery*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002199:Capillary Permeability; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D015633:Extravascular Lung Water / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011013:Pneumonectomy; D011183:Postoperative Complications / Q000276:immunology / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D003094:Collagen