I did not set out today to write about this topic but as I reviewed some of my recent blogline notices, the topic just kind of jumped out at me. I must note here that what I am about to write about probably will not seem important to you. However, it may be important to those who have a keen interest in current research on environmental illness. On this blog, we write, comment and note important research on all kinds of environmental illness, including those that are considered respiratory diseases such as emphysema and COPD. As we have noted before, the expression of Nrf2 has an important effect on the development of respiratory disease. A new study offers some more insight into the benefits of gene therapy on emphysema. As you will see, it also provides more evidence of how Nrf2 expression effects the disease.
Background: Activation of the Nrf2 pathway leads to expression of a number of different antioxidants which help to neutralize oxidative stress. Oxidative stress is produced from normal cellular metabolism but overly produced in dysfunctional cellular metabolism. Several research studies have demonstrated that in cells have an increase in oxidative stress that are deficient of Nrf2.
Late last month, it was announced that a new gene therapy may prevent the progression of emphysema. Medically speaking, this has important implications because it is estimated that 3 million suffer from emphysema which is a manifestation associated with COPD. It is characterized by accumulation of inflammatory cells in the airways and lungs. The World Health Organization expects COPD will be the 5th leading cause of illness and death by 2020 and therefore, any treatment that reduces the incidence of emphysema and COPD has important implications for public health. The researchers that developed this new type of gene therapy explain that mice lived for the duration of their life exhibiting the therapeutic effects of the gene in immune cells after the initial treatment. Generally, a genetic deficiency of a substance called A1 Anti-trypsin plays an important role in the most common form of emphysema seen in young people and this genetic deficiency not only increases the risk for early onset of lung disease but also liver cirrhosis and other health complications.
In 2005, Lizuka wrote an interesting paper that describes more about the relationship between cigarette-smoke induced emphysmena, Nrf2 and A1 anti-trypsin. As most people are aware, cigarette smoking is a major risk factor for the development of the disease and as the author notes, A1 antitrypsin deficiency is critical to its pathogenesis as it protects the body from a substance called neutrophil elastase. In mice models, deletions of the gene for something called neutraphil elastase (NE) are protected from this type of emphysema. Neutraphil elastase is key to host immune defence and assists in decreasing pathogenic virulence by attacking a protein in the pathogen's cell wall. (Belaaouaj) Consequently, the very nature of its activity can cause damage to tissue. In addition oxidative stress plays an important role by inactivating A1 antitrypsin and activating inflammatory mediators including NF-kappab leading to the production of Il-8 and TNF-a. Interestingly, this author notes other similar compounds may provide similar protection as A1 anti-trypsin. He says, "because not all smokers develop emphysema and many smokers with emphysema have normal levels of A1 antitrypsin." His findings suggest that other anti-proteases called secretory leukoprotease inhibitors (SLPI) are effective at inhibiting neutrophil elastase (NE) and NE-induced emphysema and more effective at preventing neutrophil mediated lung damage.
What is interesting about this study and this author's work is that Nrf2 is an important activator of SLPI and his findings support numerous other reports that show Nrf2 deficiency increases the risk for CS-induced emphysema. Nrf2 -/- animals show severe inflammation when exposed to cigarette smoke. In addition, other findings include a lack of induction of anti-oxidant enzymes and significantly higher levels of oxidative stress in Nrf2-/- mice. He also points out that Nrf2 activates the gene CD36 which enhances phagocytosis of apoptotic neutraphils but in Nrf2 deficient animals the number of immune cells that phagocize neutraphils was much lower. This indicates that macrophage-medicated clearance of neutraphils may be impaired in Nrf2 animals. In relation to this possible mode of action for CD36, in November 2009, a potentially important study was published. During that study, the researchers investigated the bacterial clearances of COPD patients compared to others. They found that COPD patients showed reduced phagocytic response to the two pathogens tested, S pneumoniae and H. influenza. This suggests the presence of suppression of macrophage innate responses that may lead to bacterial colonization and increased incidence of bacterial infection which is commonly found in COPD patients. (Taylor) Lizuka goes on in his paper and describes that Nrf2 deficient animals had increased levels of NE increased after exposure to cigarette smoke compared to controls even though there was little difference in A1 anti-trypsin production after cigarette smoke. His other findings include the expression of SLPI was reduced in Nrf2 -/- mice compared to wild-type Nrf2 animals and he suggested this could account for increased levels of NE. Interestingly, the known activators such as sulforphane increased expression of SLPI whereas, the activators PPAR-gamma activators did not and therefore this confirmed that SLPI is under the regulation of Nrf2. SLPI is also produced by stimuli including LPS and proinflammatory cytokines, in addition to NE and has been shown to prevent activation of the NF-kappaB pathway. This not only may explain the susceptibility of Nrf-/- mice to emphysema but also may explain their susceptibility to others pathogenic stimuli that cause disease including inflammatory lung diseases. (Ishii)
In 2008, one study linked fibromyalgia with A1 anti-trypsin deficiency but a recent study of anti-trypsin 1 conflict on whether they include inflammatory processes. Albeit, this judgement was made from a very small study. It seems for now the jury is still out on whether it does or does not. Ishii does show in one study there is evidence that A1 anti-trypsin is regulated by Nrf2 but a similiar study by the same research failed to duplicate these findings. In spite of the contradictions in the results of these studies and with the recent evidence of the link between Nrf2 and SLPI, it is worth noting that thos with a1 antitypsin fibromyalgia and are Nrf2 deficient may experience symptoms more severely. As for those who are deficient in SLPI and elevated NE, the elevations in NE may identify Nrf2 deficient phenotypes.
Original document and citations...
