Reactive oxygen species as signaling molecules in the development of lung fibrosis

Abstract

Pulmonary fibrosis is a relatively rare but devastating disease characterized by the excessive deposition of extracellular matrix. The increased matrix results in reduced lung compliance and increased work of breathing, while the obliteration of alveolar-capillary structures can result in hypoxemia and pulmonary hypertension, which manifests clinically as worsening shortness of breath, respiratory failure and death. Unbiased genome wide association studies combined with animal models suggest that damage to the alveolar epithelium is the initiating factor in pulmonary fibrosis. This epithelial injury leads to the activation and proliferation of myofibroblasts that secrete extracellular matrix proteins characteristic of fibrosis. The best described molecular link between alveolar epithelial dysfunction and myofibroblast activation and proliferation is the profibrotic cytokine transforming growth factor-β (TGF-β). We and others have found that mitochondrial and NADPH oxidase-generated reactive oxygen species (ROS) play a signaling role to enhance TGF-β signaling and promote fibrosis. This purpose of this review is to review ROS signaling downstream of the activation of TGF-β. We suggest that an improved understanding of these pathways might explain the failure of nonselective antioxidants to improve outcomes in patients with pulmonary fibrosis and might identify novel targets for therapy.

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

“…Thus, direct reads of proteome content suggest that individual cell types may differentially respond to mitochondria need and/or management in response to the challenges of chronic aging and acute stress insults. These results are consistent with the emerging importance of complex I and III on global cellular health during aging and its response through metabolic cascades including the TCA cycle (6,(34)(35)(36)(37)39,43,64,65).…”

“…Specifically, in mitochondrial pathways and related mitochondrial stress responsive pathways (60)(61)(62)(63), changes that are now implicated in the aging process from multiple perspectives. In particular, both complex I and complex III and their links to key metabolic pathways are asserted to be drivers of the aging process (6,(34)(35)(36)(37)39,43,64,65). Herein, we noted substantial changes in the expression of mitochondrial proteins involved in both complexes, with a marked increase in abundance of mitochondrial components in AM cells compared to AT2 cells, suggestive of cell specific differential responses reflecting their unique roles in the pathobiology of the aging process and differential response to chronic particulate and pathogen environmental stresses such as viral/bacterial challenge leading to pneumonia in the elderly and long-term impact on recovery (9).…”

“…The health of the mitochondria has received increased attention given its role in managing oxidative stress and intermediary metabolism in the lung (33)(34)(35)(36)(37). Recently, the lifespan extending drug, metformin, was shown to protect the lung from oxidative stress by inhibiting the activity of the mitochondrial complex I leading to a reduction in reactive oxygen species (ROS) emergent from the complex I machinery (35,38,39). It is now apparent that changes in the cellular transcriptome (3,7,40), proteome (7,40), stress-related PN pathways (2,6,17,41) and mitochondrial pathways (12,(34)(35)(36)39,(42)(43)(44)(45)(46) can have complex effects on the functionality of the lung (19,(47)(48)(49)(50)(51).…”

A Potential Link Between Oxidative Stress and Endothelial-to-Mesenchymal Transition in Systemic Sclerosis

“…In this review, we summarize the most relevant research regarding the correlation between oxidative stress and EndMT, and their role in SSc-associated vascular damage and remodeling. Readers interested in a more comprehensive discussion concerning the mechanisms involved in the onset and progression of the fibrotic process can refer to other recent excellent reviews ( 27 – 30 ).…”

Redox Balance Keepers and Possible Cell Functions Managed by Redox Homeostasis in Trypanosoma cruzi

“…In recent years, several scientists have identified new roles of redox homeostasis. It is suggested that ROS (e.g., H 2 O 2 ) at low levels serve as second messenger, and low MW thiols monitor the cellular redox state and play a decisive role in triggering physiological pathways like programmed cell death and DNA replication (Remacle et al, 1995;Gonzalez-Gonzalez et al, 2017;Lorenzen et al, 2017;Phull et al, 2018). Besides, thiol peroxidases appear to be important players in redox signaling processes.…”