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GEN News Highlights : Sep 6, 2010

Researchers Determine Proinflammatory Enzyme’s Role in Limiting Neutrophil Inflammation in the Lung

Study results indicate caution should be taken in developing drugs that inhibit this enzyme.

Scientists have deciphered how leukotriene A4 hydrolase (LTA4H) acts as a proinflammatory enzyme. The research may also provide new clues to why cigarette smoke is a significant risk factor for developing diseases of the lung such as chronic bronchitis and emphysema, according to the researchers from Imperial College London and the University of Alabama at Birmingham.

The study is published in a paper titled “A Critical Role for LTA4H in Limiting Chronic Pulmonary Neutrophilic Inflammation,” appearing in the September 2 issue of Science.

PGP is a biomarker for chronic obstructive pulmonary disease (COPD) and is implicated in neutrophil persistence in the lung. The enzymes released by neutrophils can cause particular damage in the lung, where they can attack collagen, selectively cutting out a molecular fragment known as PGP. This fragment in turn recruits more neutrophils, potentially leading to a vicious circle of damage.

The investigators found that in acute neutrophil-driven inflammation, LTA4H, which generates the inflammatory mediator leukotriene B4 (LTB4), degraded PGP and thus facilitated the resolution of inflammation. In contrast, cigarette smoke, another major risk factor for COPD, selectively inhibited LTA4H aminopeptidase activity, which led to the accumulation of PGP and neutrophils.

The researchers believe that the research may have implications for the development of new drugs aimed at treating acute and inflammatory diseases. However, as well as working to reduce inflammation, LTA4H more commonly works to promote inflammation. Therefore, drugs aimed at inhibiting the pro-inflammatory activity of LTA4H could result in preventing degradation of PGP, causing potential lung damage, they caution.