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Effects of maternal food restriction on offspring lung extracellular matrix deposition and long term pulmonary
Virender K Rehan1, Reiko Sakurai, Yishi Li
1Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, David Geffen School of Medicine at UCLA, Torrance, California, USA. vrehan@labiomed.org
Insights
Maternal food restriction causing intrauterine growth restriction (IUGR) in offspring leads to increased lung extracellular matrix proteins, elastin and alpha smooth muscle actin (aSMA). This contributes to impaired lung function and bronchial hyperresponsiveness later in life.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Biochemistry
Background:
- Intrauterine growth restriction (IUGR) is linked to increased postnatal respiratory issues.
- The underlying molecular mechanisms of respiratory compromise in IUGR offspring remain unclear.
- Extracellular matrix (ECM) alterations in the lung may contribute to long-term pulmonary dysfunction.
Purpose of the Study:
- To investigate the impact of IUGR induced by maternal food restriction (MFR) on lung ECM deposition.
- To determine if altered ECM contributes to impaired pulmonary function in IUGR offspring.
Main Methods:
- Utilized a rat model of MFR during gestation to induce IUGR.
- Analyzed lung tissue at postnatal day 21 and 9 months for elastin and alpha smooth muscle actin (aSMA) expression via Western and immunohistochemistry.
- Assessed pulmonary function (resistance and compliance) and responsiveness to methacholine challenge.
- Investigated the role of protein deficiency in lung fibroblast cultures.
Main Results:
- IUGR lungs showed increased expression and abundance of elastin and aSMA at both postnatal day 21 and 9 months compared to controls.
- IUGR offspring exhibited significantly decreased pulmonary compliance and increased responsiveness to methacholine at 9 months.
- In vitro studies suggested protein deficiency as a key driver of increased pulmonary elastin deposition.
Conclusions:
- Maternal food restriction leading to IUGR alters lung ECM composition, increasing elastin and aSMA.
- These ECM changes are associated with impaired lung function and bronchial hyperresponsiveness in IUGR offspring.
- Protein deficiency is implicated as a primary mechanism for altered ECM deposition in IUGR lungs, offering a potential explanation for compromised lung development.
Abstract:
Intrauterine growth restriction (IUGR) increases the risk of respiratory compromise throughout postnatal life. However, the molecular mechanism(s) underlying the respiratory compromise in offspring following IUGR is not known. We hypothesized that IUGR following maternal food restriction (MFR) would affect extracellular matrix deposition in the lung, explaining the long-term impairment in pulmonary function in the IUGR offspring. Using a well-established rat model of MFR during gestation to produce IUGR pups, we found that at postnatal day 21, and at 9 months (9M) of age the expression and abundance of elastin and alpha smooth muscle actin (αSMA), two key extracellular matrix proteins, were increased in IUGR lungs when compared to controls (P < 0.05, n = 6), as determined by both Western and immunohistochemistry analyses. Compared to controls, the MFR group showed no significant change in pulmonary resistance at baseline, but did have significantly decreased pulmonary compliance at 9M (P < 0.05 vs. control, n = 5). In addition, MFR lungs exhibited increased responsiveness to methacholine challenge. Furthermore, exposing cultured fetal rat lung fibroblasts to serum deprivation increased the expression of elastin and elastin-related genes, which was blocked by serum albumin supplementation, suggesting protein deficiency as the predominant mechanism for increased pulmonary elastin deposition in IUGR lungs. We conclude that accompanying the changes in lung function, consistent with bronchial hyperresponsiveness, expression of the key alveolar extracellular matrix proteins elastin and αSMA increased in the IUGR lung, thus providing a potential explanation for the compromised lung function in IUGR offspring.
