TY - JOUR
T1 - Targeting NOX enzymes in pulmonary fibrosis
AU - Hecker, Louise
AU - Cheng, Jeff
AU - Thannickal, Victor J.
N1 - Funding Information:
Although accumulating data support the concept that NOX enzymes play critical roles in fibrogenesis, no specific NOX inhibitors have been identified or tested in animal models. However, anti-oxidant strategies with NAC have shown some potential benefits []. NAC is thought to exert its function as an antioxidant via its main metabolite, cysteine, a precursor of glutathione (GSH) biosynthesis. The anti-fibrotic effects of NAC have been documented in animal models of lung fibrosis; administration of NAC in rodents led to increased levels of lung GSH in control animals and following bleomycin-induced lung injury []. Preventative therapy with NAC enhanced lung GSH content and decreased collagen accumulation following bleomycin administration [, ]. These preclinical efficacy studies led to clinical development of NAC, in which NAC therapy demonstrated clinical efficacy in IPF patients, and is one of the few phase III trials to meet the pre-determined primary end-point of the study []. In this randomized, placebo-controlled clinical trial (IFIGENIA), patients were treated with a high dose of the anti-oxidant NAC (600 mg three times daily) in addition to the standard treatment regimen (prednisone, azathioprine). The study suggested that the addition of NAC to the conventional therapy significantly slowed lung function decline after 1 year, as demonstrated by preservation of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in the NAC-treated group. However, the study showed no significant effect on survival as compared to conventional therapy alone []. Another study sponsored by the US National Institutes of Health ( www.clinicaltrials.gov ; NCT00650091: PANTHER), is currently active and will evaluate the effectiveness of NAC vs. placebo. Despite limitations of the IFIGENIA clinical trial, the development of therapeutic strategies targeting oxidative stress pathways remains promising.
Funding Information:
This work was supported by U.S. National Institutes of Health grants, R01 HL067967 (VJT), R01 HL094230 (VJT), and R01 HL086836 (JC).
PY - 2012/7
Y1 - 2012/7
N2 - Oxidative stress has been associated with a number of human fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Oxidative stress is most often defined as an imbalance between the generation of reactive oxygen species (ROS) in excess of the capacity of cells/ tissues to detoxify or scavenge them. Additionally, the regulated production of ROS participates in cellular signaling. Therapeutic strategies to treat IPF have, thus far, focused on augmenting anti-oxidant capacity. Recent studies have demonstrated a critical role for ROS-generating enzymatic systems, specifically, NADPH oxidase (NOX) family oxidoreductases in fibrotic processes. In this review, we examine the evidence for NOX isoforms in the generation and perpetuation of fibrosis, and the potential to target this gene family for the treatment of IPF and related fibrotic disorders.
AB - Oxidative stress has been associated with a number of human fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Oxidative stress is most often defined as an imbalance between the generation of reactive oxygen species (ROS) in excess of the capacity of cells/ tissues to detoxify or scavenge them. Additionally, the regulated production of ROS participates in cellular signaling. Therapeutic strategies to treat IPF have, thus far, focused on augmenting anti-oxidant capacity. Recent studies have demonstrated a critical role for ROS-generating enzymatic systems, specifically, NADPH oxidase (NOX) family oxidoreductases in fibrotic processes. In this review, we examine the evidence for NOX isoforms in the generation and perpetuation of fibrosis, and the potential to target this gene family for the treatment of IPF and related fibrotic disorders.
KW - Fibrosis
KW - NADPH oxidase
KW - Oxidative stress
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U2 - 10.1007/s00018-012-1012-7
DO - 10.1007/s00018-012-1012-7
M3 - Review article
C2 - 22618245
AN - SCOPUS:84864356954
SN - 1420-682X
VL - 69
SP - 2365
EP - 2371
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 14
ER -