Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

Area of Science:

• Biochemistry
• Cell Biology
• Pathology

Background:

• Extracellular matrix (ECM) stiffening and mechanosensitive pathway activation are key in fibrosis.
• Altered collagen nanoarchitecture significantly impacts ECM structure-function in human fibrosis.

Purpose of the Study:

• To investigate the role of hypoxia-inducible factor (HIF) pathway activation in fibrosis, independent of oxygen status (pseudohypoxia).
• To determine how HIF pathway activation influences collagen structure, cross-linking, and tissue stiffness in fibrotic conditions.

Main Methods:

• Analysis of human fibrotic tissues, bioinformatic data, and ex vivo studies.
• In vitro experiments involving fibroblast manipulation (FIH knockdown, oxidative stress).
• Assessment of HIF signaling, oxidative stress markers, and collagen modifications in cells and tissues.

Main Results:

• HIF pathway activation, termed pseudohypoxia, is critical for dysregulating collagen post-translational modification and increasing tissue stiffness in fibrosis.
• Oxidative stress and Factor Inhibiting HIF (FIH) modulation can induce pseudohypoxic HIF activation in normal fibroblasts.
• Fibroblasts from lung fibrosis patients show reduced FIH activity and increased normoxic HIF activation; HIF signaling is elevated at active fibrogenesis sites.

Conclusions:

• Oxidative stress can drive pseudohypoxic HIF activation, a critical regulator of pathogenetic collagen structure-function in fibrosis.
• HIF pathway activation is a key mechanism underlying ECM stiffening and fibrosis development, irrespective of ambient oxygen levels.