Sex Differences in Lung Fibrosis Severity and Survival Traced to SPP1 Fibrotic Factor in Study

Men have higher rates of pulmonary fibrosis than women and tend to have a poorer survival. A study showed that mice exposed to silica, a known lung fibrosis trigger, have some sex-specific differences in their expression of the fibrotic factor SPP1, indicating that female sex hormones might alter molecular characteristics of the disease.

Lung fibrosis after exposure to silica most often develops in men as an occupational consequence. Work involving sandblasting, road construction, mining, and pottery-making can expose individuals to high levels of the chemical. These occupations tend to be dominated by men, so that silicosis — the type of lung fibrosis that follows silica exposure — most often occurs in men.

Likewise, idiopathic pulmonary fibrosis affects mostly men — and women, when affected, have better survival rates — a finding mirrored in mouse models of lung fibrosis after silica exposure.

In an attempt to investigate molecular underpinnings of this difference, a research team from the University of Pittsburgh exposed both male and female mice to silica, and studied the expression of SPP1.

SPP1 is a factor involved in fibrosis development, and earlier studies have confirmed its role as a modifier of TGF-β, a main driver of fibrosis.

The study, “Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice,“ reports that after silica exposure, mice developed fibrosis, but the male mice had higher levels of SPP1 in lung tissue, broncholalveolar lavage, and serum. Female mice also had more inflammatory cells in the broncholalveolar lavage fluid.

Since earlier studies have revealed that mice that lack the factor develop less severe fibrosis after exposure to bleomycin, a chemical often used to induce fibrosis in experimental animals, the researchers also explored the effects of silica in these mutant mice.

Surprisingly, mutant male and female mice did not show any difference in amounts of inflammatory cells in the broncholalveolar lavage fluid. As reported in the journal Environmental Health Perspectives, the team, however, noted that female mice lacking the SPP1 gene had fewer inflammatory cells in the broncholalveolar lavage fluid than normal female mice. In contrast, male mice deficient in SPP1 only had lower levels of the fibrosis marker hydroxyproline in their lungs compared to normal male mice.

To further explore the sex differences, the team also treated male mice with estrogen and removed the ovaries in female mice. While the estrogen treatment did not lead to any changes in SPP1 signaling, the female mice lacking ovaries had more SPP1 in their lungs.

The study indicated that sex differences in how SPP1 is expressed might contribute to the different sensitivity of male and female mice to silica exposure. This is, however, a finding that needs further research to be of value for the development of sex-specific treatments for fibrosis.