The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer's Disease.

This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer's disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.

Twelve protections evolved for the brain, and their roles in extending its functional life.

As human longevity has increased, we have come to understand the ability of the brain to function into advanced age, but also its vulnerability with age, apparent in the age-related dementias. Against that background of success and vulnerability, this essay reviews how the brain is protected by (by our count) 12 mechanisms, including: the cranium, a bony helmet; the hydraulic support given by the cerebrospinal fluid; the strategically located carotid body and sinus, which provide input to reflexes that protect the brain from blood-gas imbalance and extremes of blood pressure; the blood brain barrier, an essential sealing of cerebral vessels; the secretion of molecules such as haemopexin and (we argue) the peptide Aß to detoxify haemoglobin, at sites of a bleed; autoregulation of the capillary bed, which stabilises metabolites in extracellular fluid; fuel storage in the brain, as glycogen; oxygen storage, in the haemoprotein neuroglobin; the generation of new neurones, in the adult, to replace cells lost; acquired resilience, the stress-induced strengthening of cell membranes and energy production found in all body tissues; and cognitive reserve, the ability of the brain to maintain function despite damage. Of these 12 protections, we identify 5 as unique to the brain, 3 as protections shared with all body tissues, and another 4 as protections shared with other tissues but specialised for the brain. These protections are a measure of the brain's vulnerability, of its need for protection. They have evolved, we argue, to maintain cognitive function, the ability of the brain to function despite damage that accumulates during life. Several can be tools in the hands of the individual, and of the medical health professional, for the lifelong care of our brains.

Vascular senescence and leak are features of the early breakdown of the blood-brain barrier in Alzheimer's disease models.

Alzheimer's disease (AD) is an age-related disease, with loss of integrity of the blood-brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies.

Remote photobiomodulation targeted at the abdomen or legs provides effective neuroprotection against parkinsonian MPTP insult.

Photobiomodulation (PBM)-the irradiation of tissue with low-intensity light-mitigates neuropathology in rodent models of Parkinson's disease (PD) when targeted at the head ('transcranial PBM'). In humans, however, attenuation of light energy by the scalp and skull necessitates a different approach. We have reported that targeting PBM at the body also protects the brain by a mechanism that spreads from the irradiated tissue ('remote PBM'), although the optimal peripheral tissue target for remote PBM is currently unclear. This study compared the neuroprotective efficacy of remote PBM targeting the abdomen or leg with transcranial PBM, in mouse and non-human primate models of PD. In a pilot study, the neurotoxin MPTP was used to induce PD in non-human primates; PBM (670 nm, 50 mW/cm2 , 6 min/day) of the abdomen (n = 1) was associated with fewer clinical signs and more surviving midbrain dopaminergic cells relative to MPTP-injected non-human primates not treated with PBM. Validation studies in MPTP-injected mice (n = 10 per group) revealed a significant rescue of midbrain dopaminergic cells in mice receiving PBM to the abdomen (~80%, p < .0001) or legs (~80%, p < .0001), with comparable rescue of axonal terminals in the striatum. Strikingly, this degree of neuroprotection was at least as, if not more, pronounced than that achieved with transcranial PBM. These findings confirm that remote PBM provides neuroprotection against MPTP-induced destruction of the key circuitry underlying PD, with both the abdomen and legs serving as viable remote targets. This should provide the impetus for a comprehensive investigation of remote PBM-induced neuroprotection in other models of PD and, ultimately, human patients.

The brain's weakness in the face of trauma: How head trauma causes the destruction of the brain.

Of all our organs, the brain is perhaps the best protected from trauma. The skull has evolved to enclose it and, within the skull, the brain floats in a protective bath of cerebrospinal fluid. It is becoming evident, however, that head trauma experienced in young adult life can cause a dementia that appears decades later. The level of trauma that induces such destruction is still being assessed but includes levels well below that which cracks the skull or causes unconsciousness or concussion. Clinically this damage appears as dementia, in people who played body-contact sports in their youth or have survived accidents or the blasts of combat; and appears also, we argue, in old age, without a history of head trauma. The dementias have been given different names, including dementia pugilistica (affecting boxers), chronic traumatic encephalopathy (following certain sports, particularly football), traumatic brain injury (following accidents, combat) and Alzheimer's (following decades of life). They share common features of clinical presentation and neuropathology, and this conceptual analysis seeks to identify features common to these forms of brain injury and to identify where in the brain the damage common to them occurs; and how it occurs, despite the protection provided by the skull and cerebrospinal fluid. The analysis suggests that the brain's weak point in the face of trauma is its capillary bed, which is torn by the shock of trauma. This identification in turn allows discussion of ways of delaying, avoiding and even treating these trauma-induced degenerations.

Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models.

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Exploring the Use of Intracranial and Extracranial (Remote) Photobiomodulation Devices in Parkinson's Disease: A Comparison of Direct and Indirect Systemic Stimulations.

In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson's disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson's disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson's disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson's disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.

K369I Tau Mice Demonstrate a Shift Towards Striatal Neuron Burst Firing and Goal-directed Behaviour.

Pathological forms of the microtubule-associated protein tau are involved in a large group of neurodegenerative diseases named tauopathies, including frontotemporal lobar degeneration (FTLD-tau). K369I mutant tau transgenic mice (K3 mice) recapitulate neural and behavioural symptoms of FTLD, including tau aggregates in the cortex, alterations to nigrostriatum, memory deficits and parkinsonism. The aim of this study was to further characterise the K3 mouse model by examining functional alterations to the striatum. Whole-cell patch-clamp electrophysiology was used to investigate the properties of striatal neurons in K3 mice and wildtype controls. Additionally, striatal-based instrumental learning tasks were conducted to assess goal-directed versus habitual behaviours (i.e., by examining sensitivity to outcome devaluation and progressive ratios). The K3 model demonstrated significant alterations in the discharge properties of striatal neurons relative to wildtype mice, which manifested as a shift in neuronal output towards a burst firing state. K3 mice acquired goal-directed responding faster than control mice and were goal-directed at test unlike wildtype mice, which is likely to indicate reduced capacity to develop habitual behaviour. The observed pattern of behaviour in K3 mice is suggestive of deficits in dorsal lateral striatal function and this was supported by our electrophysiological findings. Thus, both the electrophysiological and behavioural alterations indicate that K3 mice have early deficits in striatal function. This finding adds to the growing literature which indicate that the striatum is impacted in tau-related neuropathies such as FTLD, and further suggests that the K3 model is a unique mouse model for investigating FTLD especially with striatal involvement.

Elucidating the time course of the transcriptomic response to photobiomodulation through gene co-expression analysis.

Photobiomodulation (PBM) with low-intensity red to near infrared light elicits neuroprotection in various pre-clinical models and in some clinical contexts, yet the intracellular mechanisms triggered by PBM, and their temporal sequence of modulation, remain unclear. We aimed to address this uncertainty by mapping the temporal transcriptomic response to PBM. Human SH-SY5Y neuroblastoma cells were treated with 670 nm PBM and RNA collected a various time points over 24 h. The transcriptome was screened by RNA microarray, and gene co-expression analysis by hierarchical clustering was coupled with bioinformatics analysis to reveal the molecular systems modulated by PBM and their expression patterns over the time course. The findings suggest that PBM induces distinct early phase (up to 8 h post-PBM) and late phase (24 h post-PBM) intracellular responses. The early intracellular response features enrichment of pathways relating to transcriptional regulation and cellular stress responses, while the late intracellular response demonstrates a physiological shift to enrichment of downstream pathways such as cell death and DNA damage. These findings provide support for the hypothesis that PBM acts as a transient stressful stimulus, activating endogenous stress response pathways that in turn enhance cellular resilience. Further, the study introduces a novel method for retaining the richness of the temporal component when analysing transcriptomic time course data sets.

Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Assessment of evidence for or against contributions of Chlamydia pneumoniae infections to Alzheimer's disease etiology.

Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aß peptide may be part of the brain immune response have revived longstanding contention about the possibility of causal relationships between brain pathogens and Alzheimer's disease. Research has focused on infectious pathogens that may colonize the brain such as herpes simplex type I. Some researchers have proposed the respiratory bacteria Chlamydia pneumoniae may also be implicated in Alzheimer's disease, however this remains controversial. This review aims to provide a balanced overview of the current evidence and its limitations and future approaches that may resolve controversies. We discuss the evidence from in vitro, animal and human studies proposed to implicate Chlamydia pneumoniae in Alzheimer's disease and other neurological conditions, the potential mechanisms by which the bacterium may contribute to pathogenesis and limitations of previous studies that may explain the inconsistencies in the literature.

Photobiomodulation Mitigates Cerebrovascular Leakage Induced by the Parkinsonian Neurotoxin MPTP.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain's vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 hours after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain's vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.

"Photobiomics": Can Light, Including Photobiomodulation, Alter the Microbiome?

Objective: The objective of this review is to consider the dual effects of microbiome and photobiomodulation (PBM) on human health and to suggest a relationship between these two as a novel mechanism. Background: PBM describes the use of low levels of visible or near-infrared (NIR) light to heal and stimulate tissue, and to relieve pain and inflammation. In recent years, PBM has been applied to the head as an investigative approach to treat diverse brain diseases such as stroke, traumatic brain injury (TBI), Alzheimer's and Parkinson's diseases, and psychiatric disorders. Also, in recent years, increasing attention has been paid to the total microbial population that colonizes the human body, chiefly in the gut and the mouth, called the microbiome. It is known that the composition and health of the gut microbiome affects many diseases related to metabolism, obesity, cardiovascular disorders, autoimmunity, and even brain disorders. Materials and methods: A literature search was conducted for published reports on the effect of light on the microbiome. Results: Recent work by our research group has demonstrated that PBM (red and NIR light) delivered to the abdomen in mice, can alter the gut microbiome in a potentially beneficial way. This has also now been demonstrated in human subjects. Conclusions: In consideration of the known effects of PBM on metabolomics, and the now demonstrated effects of PBM on the microbiome, as well as other effects of light on the microbiome, including modulating circadian rhythms, the present perspective introduces a new term "photobiomics" and looks forward to the application of PBM to influence the microbiome in humans. Some mechanisms by which this phenomenon might occur are considered.

Pre-conditioning with Remote Photobiomodulation Modulates the Brain Transcriptome and Protects Against MPTP Insult in Mice.

Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100 nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. "remote PBM") also provides protection of the brain in an MPTP mouse model of Parkinson's disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670-nm light (4 J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10 days, followed by injection of the parkinsonian neurotoxin MPTP (50 mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10 days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.

Photobiomodulation of the microbiome: implications for metabolic and inflammatory diseases.

The human microbiome is intimately associated with human health, with a role in obesity, metabolic diseases such as type 2 diabetes, and divergent diseases such as cardiovascular and neurodegenerative diseases. The microbiome can be changed by diet, probiotics, and faecal transplants, which has flow-on effects to health outcomes. Photobiomodulation has a therapeutic effect on inflammation and neurological disorders (amongst others) and has been reported to influence metabolic disorders and obesity. The aim of this study was to examine the possibility that PBM could influence the microbiome of mice. Mice had their abdomen irradiated with red (660 nm) or infrared (808 nm) low-level laser, either as single or multiple doses, over a 2-week period. Genomic DNA extracted from faecal pellets was pyrosequenced for the 16S rRNA gene. There was a significant (p < 0.05) difference in microbial diversity between PBM- and sham-treated mice. One genus of bacterium (Allobaculum) significantly increased (p < 0.001) after infrared (but not red light) PBM by day 14. Despite being a preliminary trial with small experimental numbers, we have demonstrated for the first time that PBM can alter microbiome diversity in healthy mice and increase numbers of Allobaculum, a bacterium associated with a healthy microbiome. This change is most probably a result of PBMt affecting the host, which in turn influenced the microbiome. If this is confirmed in humans, the possibility exists for PBMt to be used as an adjunct therapy in treatment of obesity and other lifestyle-related disorders, as well as cardiovascular and neurodegenerative diseases. The clinical implications of altering the microbiome using PBM warrants further investigation.

Remote tissue conditioning is neuroprotective against MPTP insult in mice.

Current treatments for Parkinson's disease (PD) are primarily symptomatic, leaving a need for treatments that mitigate disease progression. One emerging neuroprotective strategy is remote tissue conditioning, in which mild stress in a peripheral tissue (e.g. a limb) induces protection of life-critical organs such as the brain. We evaluated the potential of two remote tissue conditioning interventions - mild ischemia and photobiomodulation - in protecting the brain against the parkinsonian neurotoxin MPTP. Further, we sought to determine whether combining these two interventions provided any added benefit. Male C57BL/6 mice (n = 10/group) were pre-conditioned with either ischemia of the leg (4 × 5 min cycles of ischemia/reperfusion), or irradiation of the dorsum with 670 nm light (50 mW/cm2, 3 min), or both interventions, immediately prior to receiving two MPTP injections 24 hours apart (50 mg/kg total). Mice were sacrificed 6 days later and brains processed for tyrosine hydroxylase immunohistochemistry. Stereological counts of functional dopaminergic neurons in the substantia nigra pars compacta revealed that both remote ischemia and remote photobiomodulation rescued around half of the neurons that were compromised by MPTP (p < 0.001). Combining the two interventions provided no added benefit, rescuing only 40% of vulnerable neurons (p < 0.01). The present results suggest that remote tissue conditioning, whether ischemia of a limb or photobiomodulation of the torso, induces protection of brain centers critical in PD. The lack of additional benefit when combining these two interventions suggests they may share common mechanistic pathways. Further research is needed to identify these pathways and determine the conditioning doses that yield optimal neuroprotection.

Acquired Resilience: An Evolved System of Tissue Protection in Mammals.

This review brings together observations on the stress-induced regulation of resilience mechanisms in body tissues. It is argued that the stresses that induce tissue resilience in mammals arise from everyday sources: sunlight, food, lack of food, hypoxia and physical stresses. At low levels, these stresses induce an organised protective response in probably all tissues; and, at some higher level, cause tissue destruction. This pattern of response to stress is well known to toxicologists, who have termed it hormesis. The phenotypes of resilience are diverse and reports of stress-induced resilience are to be found in journals of neuroscience, sports medicine, cancer, healthy ageing, dementia, parkinsonism, ophthalmology and more. This diversity makes the proposing of a general concept of induced resilience a significant task, which this review attempts. We suggest that a system of stress-induced tissue resilience has evolved to enhance the survival of animals. By analogy with acquired immunity, we term this system 'acquired resilience'. Evidence is reviewed that acquired resilience, like acquired immunity, fades with age. This fading is, we suggest, a major component of ageing. Understanding of acquired resilience may, we argue, open pathways for the maintenance of good health in the later decades of human life.

Role of iron in the pathogenesis of respiratory disease.

Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.