White blood cells, called neutrophils, are the first responders to injury and invading microorganisms. They differ from other white blood cells by being short-lived and loaded with destructive enzymes, which they release against invading microorganisms. Unfortunately, when neutrophils die, these enzymes leach out and can destroy healthy tissue. The normal neutophil response is self-limiting. The lung inflammation in cystic fibrosis, severe asthma, and chronic obstructive pulmonary lung disease (COPD) is associated with excessive neutrophil accumulation. Non-steroidal drugs have had limited success in controlling neutrophil-induced lung inflammation. In a report, published in the journal Science, researchers identified a major chemoattractant for neutrophils. This attractant is rapidly degraded after infections with microorganisms, but cigarette smoke prevents degradation and so causes persistent lung inflammation.
When researchers analyzed sputum samples (spittle) from patients with chronic lung diseases, they identified high concentrations of a collagen breakdown product, PGP (made up of amino acids proline-lysine-proline). They showed that PGP attracts neutrophils and can be degraded by an enzyme, called leukotriene hydrolase (LTA4H). LTA4H is interesting because it has two different activities. It generates a proinflammatory substance (LTB4) when it is inside of cells, but it has an anti-inflammatory effect by degrading PGP when found outside of cells.
Researchers infected mice with influenza virus and analyzed bronchial lavages from the infected and uninfected mice. The lavages from the infected mice, but not the control mice contained large amounts of LTA4H. No PGP was detected. The researchers then infected mice that lacked the gene for LTA4H and found that they could recover PGP in the lavages of these mice. These and similar studies suggested that PGP was rapidly degraded by LTA4H after infection with a microorganism. However, treating mice with “smoke concentrate” to simulate smoking, caused PGP to be chemically modified and then PGP accumulated in the lungs. This resulted in a large accumulation of neutrophils in the lungs of smoke-treated mice. The researchers write: “Our results also suggest that cigarette smoke shifts the emphasis of LTA4H, which has both pro- and anti-inflammatory functions, toward a proinflammatory phenotype” (Snelgrove, R.J. et al.).
The study identified both a powerful attractant for neutrophils, PGP, and the enzymatic activity that destroys PGP and helps to put an end to lung inflammation. Apparently, smoke prevents the destruction of PGP and causes large accumulation of neutrophils, which end up releasing factors or enzymes that degrade and scar lung tissue. Right now drugs are being developed that target the proinflammatory LTB4 by inhibiting LTA4H. This may not be a good idea. The researchers write: “These studies imply that therapeutic strategies inhibiting LTA4H to prevent LTB4 generation may not reduce neutrophil recruitment because of elevated levels of PGP” (Snelgrove, R.J. et al.). Treatments to rid the lung of PGP would be more effective.
Snelgrove, R.J. A Critical Role for LTA4H in Limiting Chronic Pulmonary Neutrophilic Inflammation. Science (2010) 330: 90
Barnes, P.J. Neutrophils Find Smoke Attractive. Science (2010) 330: 40