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Introduction Cutaneous leishmaniasis is caused by Leishmania parasites and exhibits a wide range of clinical manifestations, from self-healing lesions to chronic, debilitating infections (1). No vaccines exist for leishmaniasis, and [...], Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic [CD8.sup.+] T cell responses mediate disease. Although these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional [CD8.sup.+] T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdml), a transcription factor necessary for cytolytic [CD8.sup.+] T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce ROS and ultimately increased the hypoxic state and granzyme B expression in [CD8.sup.+] T cells. Importantly, lesions from patients with cutaneous leishmaniasis exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia- driven signals that support local differentiation of cytolytic [CD8.sup.+] T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as for other inflammatory skin diseases in which cytolytic [CD8.sup.+] T cells contribute to pathogenesis.

Introduction Human epidemiologic studies have shown a clear association of adverse prenatal and early postnatal development and increased risk of ischemic heart disease in adults (Barker et al. 1989). The [...], Epidemiological studies have demonstrated a relationship between the adverse influence of perinatal development and increased risk of ischemic heart disease in adults. From negative factors to which the fetus is subjected, the most important is hypoxia. The fetus may experience hypoxic stress under different conditions, including pregnancy at high altitude, pregnancy with anemia, placental insufficiency, and heart, lung, and kidney disease. One of the most common insults during the early stages of postnatal development is hypoxemia due to congenital cyanotic heart defects. Experimental studies have demonstrated a link between early hypoxia and increased risk of ischemia/reperfusion injury (I/R) in adults. Furthermore, it has been observed that late myocardial effects of chronic hypoxia, experienced in early life, may be sex-dependent. Unlike in males, perinatal hypoxia significantly increased cardiac tolerance to acute I/R injury in adult females, expressed as decreased infarct size and lower incidence of ischemic arrhythmias. It was suggested that early hypoxia may result in sex-dependent programming of specific genes in the offspring with the consequence of increased cardiac susceptibility to I/R injury in adult males. These results would have important clinical implications, since cardiac sensitivity to oxygen deprivation in adult patients may be significantly influenced by perinatal hypoxia in a sex-dependent manner. Key words: heart, perinatal hypoxia, ischemia/reperfusion injury, sex differences. Les etudes epidemiologiques ont montre un lien entre des influences defavorables du developpement perinatal et l'accroissement du risque de maladie cardiaque ischemique chez l'adulte. L'hypoxie est le plus important facteur negatif auquel le foetus puisse etre expose. Le foetus peut etre expose a un stress hypoxique dans differentes situations, comme la grossesse a une altitude elevee, la grossesse en anemie, l'insuffisance placentaire et des maladies du coeur, des poumons et des reins. L'une des agressions les plus frequentes que le foetus puisse subir au cours des stades precoces du developpement postnatal est l'hypoxie causee par des malformations cardiaques congenitales cyanotiques. Des etudes experimentales ont montre un lien entre l'hypoxie precoce et l'accroissement du risque de lesions d'ischemie/reperfusion (I/R) chez l'adulte. En outre, on a observe que des effets myocardiques tardifs de l'hypoxie chronique subie au debut de la vie pourraient varier en fonction du sexe. Contrairement a chez les males, l'hypoxie perinatale chez les femelles adultes entrainait une augmentation marquee de la tolerance du coeur aux lesions d'I/R aigues, avec une diminution de la taille de l'infarctus et de la frequence des arythmies ischemiques. On a laisse entendre que l'hypoxie precoce pourrait entrainer la programmation dependante du sexe de genes specifiques chez les rejetons et consequemment un accroissement de la susceptibilite du coeur aux lesions d'I/R chez les adultes males. Ces resultats pourraient avoir des repercussions cliniques importantes, puisque la sensibilite du coeur au manque d'oxygene chez des patients adultes pourrait etre influencee de facon notable par l'hypoxie perinatale, avec des effets variables selon le sexe. [Traduit par la Redaction] Mots-cles : coeur, hypoxie perinatale, lesions d'ischemie/reperfusion, differences entre les sexes.

We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after [N.sup.G]-nitro-L-arginine methyl ester (20.9 [+ or -] 1.1 vs. 13.7 [+ or -] 0.5 mmHg; 39.9 [+ or -] 5.0 vs. 18.3 [+ or -] 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to [K.sup.+] (1.34 [+ or -] 0.05 vs. 1.16 [+ or -] 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 [+ or -] 2.9 vs. 21.1 [+ or -] 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 [+ or -] 0.1 vs. 1.1 [+ or -] 0.2), phosphodiesterase (1.4 [+ or -] 0.1 vs. 0.7 [+ or -] 0.1), and [Ca.sup.2+]-activated [K.sup.+] channel (0.76 [+ or -] 0.16 vs. 0.30 [+ or -] 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 [+ or -] 0.26 vs. 2.22 [+ or -] 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level. pulmonary hypoxic vasoconstriction; pulmonary vascular reactivity; nitric oxide; pulmonary vasodilators; pulmonary vasoconstrictors doi: 10.1152/ajpregu.00123.2010

Hypoxic pulmonary hypertension (HPH) causes extralohar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation ([Collal.sup.R/R]). These mice and littermate controls that have normal collagen degradation ([Collal.sup.+/+]) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U-46619, Y-27632, or calcium- and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P < 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-high-strain moduli compared with hypoxia (P < 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia. biomechanics; mechanobiology; elastin; hydroxyproline; recovery doi: 10.1152/ajpheart.00493.2009.

Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS). We also determined whether Hsp90 antagonism with geldanamycin alters the agonist-induced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia. endothelial nitric oxide synthase; prostacyclin synthase; thromboxane synthase; prostanoids; arachidonic acid metabolites doi: 10.1152/ajpheart.01207.2009.

Sleep apnea (SA) is defined as intermittent respiratory arrest during sleep and affects up to 20% of the adult population. SA is also associated with an increased incidence of hypertension and peripheral vascular disease. Exposing rodents to intermittent hypoxia during sleep mimics the cyclical hypoxia/normoxia of SA. We have previously shown that in mice and rats intermittent hypoxia induces ET-1 upregulation and systemic hypertension. Furthermore, intermittent hypoxia (IH) in mice increases nuclear factor of activated T cells isoform 3 (NFATc3) transcriptional activity in aorta and mesenteric arteries, whereas the calcineurin/NFAT inhibitor cyclosporin A prevents IH-induced hypertension. More importantly, NFATc3 knockout (KO) mice do not develop IH-induced hypertension. The goals of this study were to determine the role of NFATc3 in IH-induced arterial remodeling and whether IH-induced NFATc3 activation is mediated by ET-1. Oral administration of both a dual (bosentan) and a selective endothelin receptor type A antagonist (PD155080) during 2 days of IH exposure attenuated NFAT activation in aorta and mesenteric arteries. Rho kinase inhibition with fasudil also prevented IH-induced NFAT activation. Mesenteric artery cross-sectional wall thickness was increased by IH in wild-type (WT) and vehicle-treated mice but not in bosentan-treated and NFATc3 KO mice. The arterial remodeling in mesenteric arteries after IH was characterized by increased expression of the hypertrophic NFATc3 target smooth muscle-[alpha]-actin in WT but not in KO mice. These results indicate that ET-1 is an upstream activator of NFATc3 during intermittent hypoxia, contributing to the resultant hypertension and increased wall thickness. arteries; hypertension; endothelin 1; Rho kinase doi: 10.1152/aj pheart.00341.2010.

Hypoxia plays an important role in development, cellular homeostasis, and pathological conditions, such as cancer and stroke. There is also growing evidence that hypoxia is an important modulator of the inflammatory process. Hypoxia-inducible factors (HIFs) are a family of proteins that regulate the cellular response to oxygen deficit, and loss of HIFs impairs inflammatory cell function. There is little known, however, about the role of epithelial-derived HIF signaling in modulating inflammation. Cobalt is capable of eliciting an allergic response and promoting HIF signaling. To characterize the inflammatory function of epithelial-derived HIF in response to inhaled cobalt, a conditional lung-specific HIF1[alpha], the most ubiquitously expressed HIF, deletion mouse, was created. Control mice showed classic signs of metal-induced injury following cobalt exposure, including fibrosis and neutrophil infiltration. In contrast, HIF1[alpha]-deficient mice displayed a Th2 response that resembled asthma, including increased eosinophilic infiltration, mucus cell metaplasia, and chitinase-like protein expression. The results suggest that epithelial-derived HIF signaling has a critical role in establishing a tissue's inflammatory response, and compromised HIFl[alpha] signaling biases the tissue towards a Th2-mediated reaction. deletion mouse doi: 10.1152/ajplung.00252.2009