Fig. 9: Paclitaxel (Pax) mitigates perinatal high-fat diet (HFD)-associated bronchial and vascular remodeling.

A The offspring of HFD- or standard diet (SD)-fed dams received an intravenous (i.v.) administration of vehicle or Pax, a FoxO1 activator, at postnatal day 50 (P50). All endpoints were assessed at P70. B–D Body weight (B), white adipose tissue (WAT) (C), and WAT relative to body weight (D). E Representative immunofluorescent lung images for α-smooth muscle actin (αSMA, red) and FoxO1 (green); the quantitative FoxO1 intensities per defined area (10 µm²) are displayed. F Respiratory airway resistance. G Analysis of the bronchial SMC (bSMC) layer in bronchi (diameter: 150–250 µm). H, I Complete microvascular muscularization (20–100 µm) (H). Right ventricular weight relative to body weight (I). J, K Representative immunofluorescent lung images for αSMA (red) and Ki67 (green, proliferation); the number of Ki67⁺ nuclei relative to total nuclei of αSMA-positive cells in bronchi (diameter: 150–250 µm) (J) and microvessels (20–100 µm) (K). Values are shown under the respective images. Data are shown as mean ± standard error of the mean. B–K SD n = 3–7, HFD n = 3–5; two-sided Mann–Whitney test and two-sided Student’s t test; *P < 0.05; ***P < 0.001; ****P < 0.0001. Black = SD + vehicle; white = HFD + vehicle; beige = SD + Paclitaxel; red = HFD + Paclitaxel. A detailed list of sample sizes and P value per graph is provided in the Supplemental Material. Source data are provided as a Source Data file. L Proposed working model: effects of HFD-induced maternal and perinatal obesity with early-onset offspring obesity and elevated circulating levels of the adipocytokine Interleukin (IL)-6 on the developing lung. During lung development, this chronic subacute inflammatory state promotes the activation of STAT3 and AKT signaling in the lung and the proliferation of smooth muscle cells (SMC) via the cytoplasmatic sequestration of the transcription factor FoxO1. Bronchial and vascular SMC hyperproliferation is ultimately related to bronchial obstruction and pulmonary hypertension, respectively. Both IL-6 deficiency and FoxO1 activation prevent these structural and functional impairments of the bronchi and vessels after perinatal obesity, suggesting an IL-6-STAT3-AKT-FoxO1 axis and a new therapeutic approach to mitigate the early metabolic origins of chronic lung diseases (CLDs). The illustration has been created by the authors.