Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis

Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L510-8. doi: 10.1152/ajplung.00122.2011. Epub 2011 Jul 8.


Fibrotic interstitial pneumonias are more prevalent in males of advancing age, although little is known about the underlying mechanisms. To evaluate the contributions of age and sex to the development of pulmonary fibrosis, we intratracheally instilled young (8-12 wk) and aged (52-54 wk) male and female mice with bleomycin and assessed the development and severity of fibrotic lung disease by measurements of lung collagen levels, static compliance, leukocyte infiltration, and stereological quantification of fibrotic areas in histological sections. We also quantified proinflammatory and profibrotic chemokine and cytokine levels in the bronchoalveolar lavage fluid. Aged male mice developed more severe lung disease, indicated by increased mortality, increased collagen deposition, and neutrophilic alveolitis compared with aged female mice or young mice of either sex. Aged male mice also exhibited increased levels of transforming growth factor-β, IL-17A, and CXCL1 in their bronchoalveolar lavage fluid. Young male mice developed a more fibrotic disease after bleomycin instillation compared with female mice, regardless of age. There was no difference in fibrosis between young and aged female mice. Taken together, these findings suggest that the variables of advanced age and male sex contribute to the severity of pulmonary fibrosis in this model. Our findings also emphasize the importance of stratifying experimental groups on the basis of age and sex in experimental and epidemiological studies of this nature.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Bleomycin / administration & dosage*
  • Bleomycin / adverse effects
  • Bronchoalveolar Lavage Fluid / chemistry
  • Chemokine CXCL1 / analysis
  • Chemokine CXCL1 / biosynthesis
  • Collagen / analysis
  • Collagen / biosynthesis
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Lung / drug effects*
  • Lung / pathology
  • Lung Compliance
  • Lung Injury / chemically induced
  • Lung Injury / genetics*
  • Lung Injury / metabolism
  • Lung Injury / mortality
  • Lung Injury / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / mortality
  • Pulmonary Fibrosis / pathology*
  • Sex Characteristics
  • Sex Factors
  • Survival Rate
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / biosynthesis
  • Trauma Severity Indices


  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Transforming Growth Factor beta
  • Bleomycin
  • Collagen