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.

During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers.

No abstract

Rationale While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated. Objective We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants. Methods and Results Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4+ and CD8+ T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4+ T cells and complement are independently sufficient to cause graft ischemia. CD8+ T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia × time duration) and the development of subsequent airway remodeling. Conclusions These studies demonstrated that CD4+ T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.

Rationale: Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.Objectives: To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism.Methods: Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/ hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling. Measurements and Main Results:In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1.Conclusions: Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.

Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B 4 (LTB 4 ). LTB 4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB 4 was functionally bimodal: Lower LTB 4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB 4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB 4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB 4 stimulated, whereas high concentrations of LTB 4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1 −/− mice were refractory to the beneficial effects of LTB 4 antagonism, suggesting that LTB 4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB 4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB 4 is a promising drug target for the treatment of acquired lymphedema.

Estrogens promote cell proliferation and metastases in several human cancers. Here, we describe a different action of estrogens likely to contribute to tumor development-blocking immunosurveillance. In breast cancer cells, increasing concentrations of estrogen induce increasing levels of the granzyme B inhibitor, SerpinB9/proteinase inhibitor 9 (PI-9) and progressively block cell death induced by NK92 natural killer (NK) cells, but do not block killing by a second NK cell line, NKL cells. RNA interference knockdown of PI-9 abolishes estrogen's ability to block NK92 cell-induced cytotoxicity. Expressing elevated levels of estrogen receptor a (ERa) increases the induced level of PI-9, and makes tamoxifen (TAM), but not raloxifene or ICI 182,780, a potent inducer of PI-9. At elevated levels of ERa, induction of PI-9 by estradiol or TAM blocks killing by both NK92 and NKL cells. When the Erk pathway is activated with epidermal growth factor, the concentration of estrogen required to induce a protective level of PI-9 is reduced to 10 pM. Elevated concentrations of estrogen and ER may provide a dual selective advantage to breast cancer cells by controlling PI-9 levels and thereby blocking immunosurveillance. Expressing elevated levels of ERa reveals a potentially important difference in the effects of TAM, raloxifene and ICI 182,780 on immunosurveillance in breast cancer.

The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Recent investigation has demonstrated the mechanistic role of leukotriene B (LTB) in the molecular pathogenesis of lymphedema. LTB, a product of the innate immune response, is a constituent of the eicosanoid inflammatory mediator family of molecules that promote both physiological and pathological inflammation. Here we provide an overview of lymphatic development, the pathophysiology of lymphedema, and the role of leukotrienes in lymphedema pathogenesis.