Blocking Macrophage Leukotriene B4 Prevents Endothelial Injury and Reverses Pulmonary Hypertension

In a rat model of pulmonary hypertension, inhibition of LTB4 synthesis in macrophages that accumulate in lung tissue reverses the disease. 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. Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)–endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease–associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.