Extracellular Matrix Stiffness in Lung Health and Disease

Abstract

The extracellular matrix (ECM) provides structural support and imparts a wide variety of environmental cues to cells. In the past decade, a growing body of work revealed that the mechanical properties of the ECM, commonly known as matrix stiffness, regulate the fundamental cellular processes of the lung. There is growing appreciation that mechanical interplays between cells and associated ECM are essential to maintain lung homeostasis. Dysregulation of ECM-derived mechanical signaling via altered mechanosensing and mechanotransduction pathways is associated with many common lung diseases. Matrix stiffening is a hallmark of lung fibrosis. The stiffened ECM is not merely a sequelae of lung fibrosis but can actively drive the progression of fibrotic lung disease. In this article, we provide a comprehensive view on the role of matrix stiffness in lung health and disease. We begin by summarizing the effects of matrix stiffness on the function and behavior of various lung cell types and on regulation of biomolecule activity and key physiological processes, including host immune response and cellular metabolism. We discuss the potential mechanisms by which cells probe matrix stiffness and convert mechanical signals to regulate gene expression. We highlight the factors that govern matrix stiffness and outline the role of matrix stiffness in lung development and the pathogenesis of pulmonary fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We envision targeting of deleterious matrix mechanical cues for treatment of fibrotic lung disease. Advances in technologies for matrix stiffness measurements and design of stiffness-tunable matrix substrates are also explored.

Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

“…S13). Several reports have shown that ECM stiffness can trigger abnormal integrin signalling and mitochondrial dysfunction, thereby contributing to the development of disorders such as COPD, lung fibrosis, and emphysema 11,40–42 . These results are consistent with our present finding that isoDGR-modified ECM proteins promote age-linked mitochondrial dysfunction in Pcmt1 -/- mouse lung, whereas targeted antibody therapy can induce immune clearance of this damage motif and restore normal metabolic activity.…”

“…S13). Several reports have shown that ECM stiffness can trigger abnormal integrin signalling and mitochondrial dysfunction, thereby contributing to the development of disorders such as COPD, lung fibrosis, and emphysema 11,[40][41][42] .…”

Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease

“…The stiffness of ECM is typically reported as elastic modulus (E, also known as Young’s modulus) or shear modulus (G). Several mechanical test methods have been used to measure the ECM mechanical property, including atomic force microscopy, ultrasound elastography, magnetic resonance elastography, and fluorescent microscopy ( Guo et al, 2022 ). The accumulated evidence revealed that ECM stiffening, a symbol of tissue fibrosis, is not merely an epiphenomenon of liver fibrosis, but can actively promote dysregulation of cellular function, leading to persistent and/or progressive liver fibrosis ( Chen et al, 2019 ).…”

Extracellular‐Matrix Mechanics Regulate the Ocular Physiological and Pathological Activities

“…Tere is growing evidence that external mechanical factors impact the confguration of biomacromolecules, the fate of cells, and the structure of tissues [4,5]. Te extracellular matrix (ECM) is a common scafold for maintaining the homeostasis of tissues and organs [6]. It forms a complex but highly organized network and is remodeled dynamically around cells that not only provides mechanical support for the completeness and resilience of cells but also modulates cell homeostasis and signal transduction [7][8][9].…”