Bleomycin induced lung fibrosis increases work of breathing in the mouse.
Bleomycin induces a transient lung fibrosis in mice that has been used to investigate mechanisms related to idiopathic pulmonary fibrosis. Our aim was to determine a sensitive method for assessing lung function in bleomycin treated mice that correlated with the degree of lung fibrosis as measured by collagen immunohistochemistry. Bleomycin (2 U/kg) or saline was intratracheally microsprayed to male C57BL/6 mice under isoflurane anesthesia. Lung function (single compartment model, constant phase model, and work of breathing) was assessed using the flexiVent system, and after euthanasia lungs were inflated with formalin in situ for histological analysis. The lung fibrosis histopathology score for the bleomycin treated animals on day 21 was indicative of mild-to-moderate fibrosis (Saline treated control: 0 ± 0, Bleomycin treated: 4.9 ± 0.4). There were at least three large areas of fibrosis in the peribronchial alveolar regions of the lung, but less than 50% of each lung was affected by fibrosis. Although changes in lung function were less obvious, volume normalized dynamic work of breathing measured at 30 ml/kg tidal volume (Saline treated control: 9.2 ± 0.1 J/l, Bleomycin treated: 10.6 ± 0.3 J/l) and the oscillatory mechanics constant phase model parameter tissue elastance (H; Saline treated control: 31 ± 2 cm H(2)O/ml, Bleomycin treated: 38 ± 3 cm H(2)O/ml) were significantly increased on day 21. The work of breathing (r = 0.83) correlated slightly better with fibrosis histopathology score than H (r = 0.64). Work of breathing can detect decrements in lung function due to pulmonary fibrosis, correlates well with the amount of collagen in the lungs, and may be a more sensitive quantitative measure of efficacy for drugs being developed to treat pulmonary fibrosis.
Hoffmann-La Roche, pRED, Pharma Research & Early Development, DTA Inflammation, 340 Kingsland Street, Nutley, NJ 07110, USA. Jonathan.phillips@roche.com
Jonathan E
JE
Phillips
Ruoqi
R
Peng
Lisa
L
Burns
Paul
P
Harris
Rosario
R
Garrido
Gaurav
G
Tyagi
Jay S
JS
Fine
Christopher S
CS
Stevenson
D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012129:Respiratory Function Tests; D014939:Work of Breathing / Q000276:immunology / Q000502:physiology*
D018836:Inflammation Mediators; D001761:Bleomycin