Research ArticlePulmonary Hypertension

Blocking Macrophage Leukotriene B4 Prevents Endothelial Injury and Reverses Pulmonary Hypertension

Science Translational Medicine  28 Aug 2013:
Vol. 5, Issue 200, pp. 200ra117
DOI: 10.1126/scitranslmed.3006674

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How to Open a Blocked Vessel

Like the pressure that builds up in a kinked garden hose, pulmonary hypertension occurs when the blood vessels in the lung become occluded. This hard-to-treat disease can arise in various settings, sometimes along with collagen vascular disease or HIV infection. It ultimately leads to heart failure as the heart tries to pump against higher resistance. Now, Tian and her colleagues show that certain types of pulmonary hypertension may be caused by a leukotriene B4 (LTB4) released from the macrophages that accumulate in lung tissue and that interruption of this process can reverse the disease. Although much of their evidence comes from a rat model of hypertension, the same may be true of some patients as well.

Treatment of athymic rats with the tyrosine kinase inhibitor SU5416 causes them to acquire pulmonary hypertension. At the same time, macrophages gather around the small arterioles of the lung and synthesize an excess amount of LTB4. This leukotriene injures the endothelial cells of the nearby vessels, causing apoptosis while simultaneously provoking abnormal proliferation of the smooth muscle cells. This excess cell division results in arterial occlusion and hypertension. The authors found that damping down excess LTB4 by inhibiting its biosynthesis could reverse disease: In treated animals, cardiac function improved and obstructed arterioles opened.

These results may apply to certain patients with pulmonary hypertension: Among a group of 19 patients, those that had pulmonary hypertension secondary to a connective tissue disease generally show higher LTB4 in serum. The next step will be to see whether therapies directed toward the LTB4 signaling system can help to clear the arterioles in patients with pulmonary hypertension, at least in those with associated inflammation.