Neurotrophins (NTs) are a family of growth factors that are well-known in the nervous system. There is increasing recognition that NTs (nerve growth factor, brain-derived neurotrophic factor and NT3) and their receptors (high-affinity TrkA, TrkB and TrkC, and low-affinity p75NTR) are expressed in lung components including the nasal and bronchial epithelium, smooth muscle, nerves and immune cells. NT signaling may be important in normal lung development, developmental lung disease, allergy and inflammation (e.g., rhinitis, asthma), lung fibrosis and even lung cancer. In this review, we describe the current status of our understanding of NT signaling in the lung, with hopes of using aspects of the NT signaling pathway in the diagnosis and therapy of lung diseases.

These results indicate that NTs acutely modulate pulmonary endothelial NO production and contribute to relaxation of the pulmonary vasculature.

RA. Hypoxia-induced mitogenic factor (FIZZ1/RELM␣) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELM␣) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH. endothelial apoptosis; T-helper type 2 inflammation; human resistin PULMONARY HYPERTENSION (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right-sided heart failure. It is associated with significant morbidity and mortality. Despite major advances in diagnosis and treatment of this disease over the last several decades, the underlying mechanisms of PH remain enigmatic. In humans, severe pulmonary arterial hypertension (PAH, idiopathic PH) is characterized by plexiform lesions that contain phenotypically altered pulmonary smooth muscle and endothelial cells (ECs) (56). Evidence suggests that early EC apoptosis may trigger both degenerative and reactive proliferative events that result in the pulmonary vascular pathology of PH (25). Failure to stop the initial repair response could result in pathophysiological vascular remodeling, such as that which occurs during PH (25). Strong circumstantial clinical evidence supports an immune pathogenesis of PH, but whether the immunological features are a cause or consequence of PH is unknown. It has been shown that vascular endothelial growth factor (VEGF) receptor (VEGFR) blockade with Su...

Objective Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or RELMα) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/−) mice. HIMF-induced PH was significantly diminished in HIF-1α+/− mice and was accompanied by a dysregulated VEGF-A–VEGF receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β (RELMβ), significantly increased IL-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human RELMβ significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6–expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, VEGF-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

Although sex differences in asthma severity are recognized, the mechanisms by which sex steroids such as estrogen influence the airway are still under investigation. Airway tone, a key aspect of asthma, represents a balance between bronchoconstriction and dilation. Nitric oxide (NO) from the bronchial epithelium is an endogenous bronchodilator. We hypothesized that estrogens facilitate bronchodilation by generating NO in bronchial epithelium. In acutely dissociated human bronchial epithelial cells from female patients exposure to 17␤-estradiol (E 2 ; 10 pM-100 nM) resulted in rapid increase of diaminofluorescein fluorescence (NO indicator) within minutes, comparable with that induced by ATP (20 M). Estrogen receptor (ER) isoform-specific agonists (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC) (ER␣) and diaryl-propionitrile (DPN) (ER␤) stimulated NO production to comparable levels and at comparable rates, whereas the ER antagonist 7␣,17␤-[9- [(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780) (1 M) was inhibitory. Estrogen effects on NO were mediated via caveolin-1 (blocked using the caveolin-1 scaffolding domain peptide) and by increased intracellular calcium concentration [prevented by 20 M 1,2-bis(oaminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid tetra(acetoxymethyl) ester but not by blocking Ca 2ϩ influx using LaCl 3 ]. Estrogen increased endothelial NO synthase activation (inhibited by 100 M N G -nitro-L-arginine methyl ester) and phosphorylated Akt. In epithelium-intact human bronchial rings contracted with acetylcholine (1 M), E 2 , THC, and DPN all produced acute bronchodilation in a dose-dependent fashion. Such bronchodilatory effects were substantially reduced by epithelial denudation. Overall, these data indicate that estrogens, acting via ER␣ or ER␤, can acutely produce NO in airway epithelium (akin to vascular endothelium). Estrogen-induced NO and its impairment may contribute to altered bronchodilation in women with asthma.