Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

Abstract

Obesity is a pre-disposing condition for chronic obstructive pulmonary disease, asthma, and pulmonary arterial hypertension. Accumulating evidence suggests that metabolic influences during development can determine chronic lung diseases (CLD). We demonstrate that maternal obesity causes early metabolic disorder in the offspring. Here, interleukin-6 induced bronchial and microvascular smooth muscle cell (SMC) hyperproliferation and increased airway and pulmonary vascular resistance. The key anti-proliferative transcription factor FoxO1 was inactivated via nuclear exclusion. These findings were confirmed using primary SMC treated with interleukin-6 and pharmacological FoxO1 inhibition as well as genetic FoxO1 ablation and constitutive activation. In vivo, we reproduced the structural and functional alterations in offspring of obese dams via the SMC-specific ablation of FoxO1. The reconstitution of FoxO1 using IL-6-deficient mice and pharmacological treatment did not protect against metabolic disorder but prevented SMC hyperproliferation. In human observational studies, childhood obesity was associated with reduced forced expiratory volume in 1 s/forced vital capacity ratio Z-score (used as proxy for lung function) and asthma. We conclude that the interleukin-6-FoxO1 pathway in SMC is a molecular mechanism by which perinatal obesity programs the bronchial and vascular structure and function, thereby driving CLD development. Thus, FoxO1 reconstitution provides a potential therapeutic option for preventing this metabolic programming of CLD.

Characterizing and Quenching Autofluorescence in Fixed Mouse Adrenal Cortex Tissue

“…MaxBlock is a commercialized AF treatment designed to reduce background AF on paraffin-embedded and frozen tissue sections. It has been used to diminish AF in several tissues, such as the liver [ 56 ], heart [ 57 ], lung [ 58 , 59 ], pancreas [ 60 ], and skin [ 61 ] tissues.…”

The Identification of Key Genes and Biological Pathways in Polycystic Ovary Syndrome and its Complications by Next Generation Squancing (NGS) and Bioinformatics Analysis

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The importance of translational science within the respiratory field

“…Perinatal obesity enhanced the DNA damage response, transcriptional stress and ageing-associated pathways [ 25 ]. IL-6 emerged as a central modulator of these effects, as substantiated by the protection observed in IL-6-null mice and pharmacologically inhibited IL-6 signalling against the repercussions of perinatal obesity [ 26 ]. The second speaker, Mina Ali (Denmark), delivered several insightful observations underscoring the perils of a westernised dietary pattern during pregnancy [ 27 ], manifesting as an augmented risk of recurrent wheezing, asthma-like symptoms, childhood asthma and the number of exacerbations in the offspring [ 28 ].…”