Consideration must be given to both the tissues themselves a

Consideration must be given to both the tissues themselves and to infiltrating immune cells. As highlighted by Maxwell and Eckardt [88], clinical trials of compounds targeting these pathways will require large numbers of participants and prolonged follow-up to identify rare and late complications or side effects. Despite this, the potential benefits of these strategies are enormous, with implications for the treatment of many inflammatory conditions.
Introduction Hypoxia is a common abiotic stressor in freshwater habitats and although hypoxic episodes can occur naturally with daily and seasonal oscillations, they are also exacerbated by anthropogenic activities and pollutants (Jean-Philippe et al., 2015). Fish have various biochemical, physiological, and behavioural responses that enable them to survive in the presence of low oxygen levels; many of these responses are associated with changes in gene PNU-120596 receptor presumably through the activity of the family of hypoxia-inducible transcription factors (Köblitz et al., 2015). Several hypoxia-inducible factors (HIFs) have been identified in fish and are considered the master transcriptional regulators of genes involved in both the cellular and systemic responses to hypoxia (Soitamo et al., 2001; Powell and Hahn, 2002; Law et al., 2006; Rahman and Thomas, 2007). The main HIF is thought to be HIF-1, which is conserved across all organisms studied from Caenorhabditis elegans to humans (Hu et al., 2003). It is a heterodimeric complex made up of the constitutively expressed and abundant HIF-1β (Huang et al., 1996) and the oxygen-sensitive HIF-1α. At normal oxygen levels, HIF-1α is bound to von Hippel-Lindau tumour suppressor (pVHL) which is targeted for ubiquitination and proteosomal degradation. Hypoxia inhibits the degradation of HIF-1α, allowing it to accumulate and dimerise with HIF-1β, translocate to the nucleus and bind to DNA altering the expression of HIF-1-responsive genes (Kajimura et al., 2005). Target genes include, but are not limited to: vascular endothelial growth factor (vegf) that is involved in angiogenesis, erythropoietin (epo) which promotes red blood cell differentiation (Semenza, 1999), insulin-like growth factor binding protein 1 (igfbp1) that can inhibit growth and development through the binding of insulin-like growth factors (Igfs) (Kajimura et al., 2005), and most glycolytic genes (Bruick, 2003; Semenza, 2001). Beyond its role in hypoxia, HIF-1α has been shown to play a critical role in vertebrate developmental processes, including vascularisation and cardiac morphogenesis (Iyer et al., 1998; Kotch et al., 1999). hif-1α knockout mice displayed defects in vascularisation, cardiac morphogenesis and increased cephalic mesenchyme cell death (Iyer et al., 1998), with arrested embryonic development occurring between stages E8 and E11, resulting in lethality by embryonic stage E10.5 (Kotch et al., 1999). Combined, this work suggests that HIF-1α plays an essential role in mammalian embryonic development. Köblitz et al. (2015) demonstrated that multiple HIF proteins are also present in developing zebrafish embryos, but their role in normal developmental processes in embryonic and larval fish have yet to be examined. Early life stages are often the most vulnerable to stress and even brief episodes of hypoxia can have severe detrimental effects (Podrabsky and Culpepper, 2012). The effect of hypoxia on development has been examined in several species of fish, demonstrating that even acute exposure to hypoxia can result in impaired early stage development, decreased survival, delayed or abnormal development, early hatching and increased mortality (Altimiras and Phu, 2000; Bradford and Seymour, 1988; Podrabsky and Culpepper, 2012). Observed effects varied with the age and species of the fish, and the severity and duration of the hypoxic event. Embryonic Atlantic salmon (Salmo salar) exposed to hypoxia exhibited developmental delays which became more severe as development progressed (Hamor and Garside, 1976). Similar developmental delays were observed in zebrafish (Danio rerio) embryos, potentially due to alterations in apoptosis under hypoxic conditions (Shang and Wu, 2004). Although exposure to hypoxia can result in developmental abnormalities during both the embryonic and larval periods, several studies have demonstrated that fishes can respond to acute hypoxic episodes either behaviourally or physiologically. Little skate (Leucoraja erinacea) embryos responded to hypoxia with a divergent physiological and behavioural response that resulted in the decoupling of aerobic metabolism and activity, by decreasing oxygen consumption and increasing their activity within the egg case to facilitate ventilation (Di Santo et al., 2016). In zebrafish, hypoxia-induced retardation of development and growth were found to be mediated in part by activation of the HIF-1 pathway, as evidenced by an up-regulation of HIF-1 target genes such as igfbp1 (Kajimura et al., 2006) and ldha (Ton et al., 2003). Moreover, Robertson et al. (2014) demonstrated that larval and juvenile zebrafish had increased hypoxia tolerance when the HIF pathway had been activated during embryogenesis. HIF-1 is not only necessary for normal development and a hypoxia response, but its induction during development is also likely to have long-term consequences for hypoxia tolerance and survival.