Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic exposure to cigarette smoke (CS) generally confronts cellular defense systems with one of the strongest known environmental challenges. In particular, the continuous exposure of tissues of the respiratory tract to abundant concentrations of radicals; volatile compounds of the gas phase, mainly reactive oxygen and nitrogen species; and CS condensate deposits trigger a pleiotropic adaptive response, generally aimed at restoring tissue homeostasis. As documented by numerous studies published over the past decade, a hallmark of this defense system is the activation of the transcription factor NF-E2-related factor 2 (Nrf2), which, consequent to its established role as master regulator of the cellular antioxidant response, has been shown to orchestrate the first line of defense against cell- and tissue-damaging components present in CS. The key to CS-dependent Nrf2 activation is assumed to be based on the long-known phenomenon of a general strong sulfhydryl (-SH) reactivity inherent to CS. This chemical trait is virtually predestined to be sensitized by the major route leading to Nrf2 activation, characterized by its dependence on the interaction of electrophiles with specific cysteine residues inherited by Nrf2's negative cytosolic regulator Keap1 (Kelch-like ECH-associated protein 1). In addition, other pathways involving CS-activated protein kinases implicated in the upstream regulation of Nrf2, such as protein kinase C, represent an alternative/complementary mechanism of CS-induced Nrf2 activation. Because of the outstanding function of the Nrf2-Keap1 axis in defending cells and tissues against oxidant and chemical stress, either directly or indirectly via cross-talking with other defense pathways, changes in the Nrf2 or Keap1 genotype have long been associated with disease development. In terms of the two major smoking-related diseases of the lung, that is, emphysema and lung cancer, a fully functional Nrf2 genotype seems to be necessary, although not sufficient by itself, to protect the smoker from acquiring emphysema. Contrasting with this protective role, however, Nrf2 function may be potentially fatal in smoking-related lung tumorigenesis: as concluded from recent clinical investigations, lung tumor tissues harbor increased mutation or, alternatively, aberrant expression rates in either the KEAP1 or the NRF2 gene, generally resulting in constitutive Nrf2 activation, suggesting that "abuse" of Nrf2 function is an advantageous strategy of the (developing) tumor to protect itself against oxidative stress in general. On the basis of the fundamental significance of the Nrf2 pathway in smoking-dependent disease development, several attempts have been described for dietary and pharmacological intervention, the majority of which are intended to activate Nrf2 aiming at emphysema prevention. The intention of this review is to compile and discuss the various aspects of CS-Nrf2/Keap1 interaction in terms of mechanism, disease development, and chemoprevention.
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PMID:Nrf2: friend and foe in preventing cigarette smoking-dependent lung disease. 2268 25

The transcription factor, nuclear factor (NF), erythroid-derived 2-related factor 2 (NRF2), was discovered nearly 2 decades ago. Since then, over 4,000 papers have been published on NRF2 function in diverse biological systems, and it has been found to be a critical regulator of antioxidant and defense genes with antioxidant response elements in their promoters. NRF2 is particularly important in protecting cells and tissues under highly oxidative microenvironments, including the airways that interface with the external environment and are exposed to pollutants and other oxidant stressors. Using mice with targeted deletion of Nrf2, a protective role for this transcription factor has been determined in many model diseases, including acute lung injury, emphysema, allergy and asthma, pulmonary fibrosis, and respiratory syncytial virus disease. Recent studies have also found that murine Nrf2 is important in lung development and protection against neonatal lung injury. Moreover, functional polymorphisms in human NRF2 have been known to associate with disease severity, indicating a potentially important protective function. However, there is also a "dark side" to NRF2 function, as it has been found to enhance advanced stages of carcinogenesis in the lung and some other tissues. NRF2 inducers such as phytochemical isothyocyanates and synthetic triterpenoids, have been discovered and used in model systems of oxidant-induced lung diseases, and data suggest a potential for clinical interventions. Future investigations of NRF2 should yield further insight into its contribution to normal and pathophysiological conditions in the airways, and alternative treatment strategies to protect against oxidative respiratory disease.
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PMID:Noblesse oblige: NRF2 functions in the airways. 2478 56