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 epithelialderived HIF in response to inhaled cobalt, a conditional lung-specific HIF1␣, 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␣-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 HIF1␣ signaling biases the tissue towards a Th2-mediated reaction. deletion mouse LUNG DISEASES, including chronic obstructive pulmonary disease and asthma, involve a large inflammatory component. The lung's response to allergens involves a complex interplay between resident inflammatory and epithelial cells, cytokine signaling, and the environmental conditions within the tissue. One of the critical environmental features that can impact the inflammatory process is hypoxia.Hypoxia, a decrease in available oxygen reaching the tissues of the body, has profound cellular and metabolic consequences. The cellular response to hypoxia is regulated by a family of transcription factors called the hypoxia-inducible factors (HIFs) (3). HIFs are primarily regulated at the level of protein stability by a family of prolyl hydroxylases. These prolyl hydroxylase domain (PHD) proteins are members of a broader family of non-heme, iron-, and 2-oxoglutarate-dependent dioxygenases (7). Cobalt has been shown to inhibit PHDs, and this inhibition causes very similar transcriptional outputs to that of hypoxia (24,28). Recent research using human peripheral blood mononuclear cells has shown that this transcriptional overlap applies to tungsten carbide-cobalt particles, linking hard metal lung disease to hypoxia signaling (17).HIF1␣ is the most ubiquitously expressed and widely studied HIF isoform. HIF1␣ heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1␤) forming the functional transcription factor HIF1. HIF1 regulates the expression of more than 100 genes, including genes for glycolytic enzymes, sugar transporters, and proangiogenic and inflammatory factors (8,13,18,25). Moreover, HIF1␣ has also been shown to modulate inflammation indirectly by influencing the NF-B ...

Air pollution is a critical factor in the development and exacerbation of pulmonary diseases. Ozone, automobile exhaust, cigarette smoke, and metallic dust are among the potentially harmful pollution components that are linked to disease progression. Transition metals, such as cobalt, have been identified at significant levels in air pollution. Cobalt exerts numerous biological effects, including mimicking hypoxia. Similar to hypoxia, cobalt exposure results in the stabilization of hypoxia-inducible factors (HIFs), a family of proteins that regulate the cellular response to oxygen deficit. HIFs also play an important role in innate immunity and inflammatory processes. To characterize the role of HIF1alpha, the most ubiquitously expressed HIF, in the early events during cobalt-induced lung inflammation, an inducible lung-specific HIF1alpha deletion model was employed. Control mice showed classical signs of metal-induced injury following cobalt exposure, including neutrophilic infiltration and induction of Th1 cytokines. In contrast, HIF1alpha-deficient mice exhibited pronounced eosinophil counts in bronchoalveolar lavage fluid and lung tissue complemented with Th2 cytokine induction. The timing of these results suggests that the loss of epithelial-derived HIF1alpha alters the lung's innate immune response and biases the tissue toward a Th2-mediated inflammation.

Droughts are projected to increase in intensity and frequency with the rise of global mean temperatures. However, not all drought indices equally capture the variety of influences that each hydrologic component has on the duration and magnitude of a period of water deficit. While such indices often agree with one another due to precipitation being the major input, heterogeneous responses caused by groundwater recharge, soil moisture memory, and vegetation dynamics may lead to a decoupling of identifiable drought conditions. As a semi-arid basin, the Limpopo River Basin (LRB) is a severely water-stressed region associated with unique climate patterns that regularly affect hydrological extremes. In this study, we find that vegetation indices show no significant long-term trends (S-statistic 9; p-value 0.779), opposing that of the modeled groundwater anomalies (S-statistic -57; p-value 0.05) in the growing season for a period of 18 years (2004–2022). Although the Mann-Kendall time series statistics for NDVI and drought indices are non-significant when basin-averaged, spatial heterogeneity further reveals that such a decoupling trend between vegetation and groundwater anomalies is indeed significant (p-value < 0.05) in colluvial, low-land aquifers to the southeast, while they remain more coupled in the central-west LRB, where more bedrock aquifers dominate. The conclusions of this study highlight the importance of ecological conditions with respect to water availability and suggest that water management must be informed by local vegetation species, especially in the face of depleting groundwater resources.