21 research outputs found
Hypoxia and reprogramming of host pathogen interactions
No full textHighlights:• This review aims to give an overview of the simultaneous effect of hypoxia on both the host and invading pathogens. • Particular focus is given to the novel concept of hypoxic reprogramming of the innate and adaptive immune response. • Finally, it includes a brief description of the effect of low oxygen availability on pathogenicity with an emphasis on the Pseudomonas species. <br/
Hypoxia. Hypoxia, hypoxia inducible factor and myeloid cell function
No full textWith little in the way of effective therapeutic strategies to target the innate immune response, a better understanding of the critical pathways regulating neutrophil and macrophage responses in inflammation is key to the development of novel therapies. Hypoxia inducible factor (HIF) was originally identified as a central transcriptional regulator of cellular responses to oxygen deprivation. However, the HIF signalling pathway now appears, in myeloid cells at least, to be a master regulator of both immune cell function and survival. As such, understanding the biology of HIF and its regulators may provide new approaches to myeloid-specific therapies that are urgently needed
The Anti-Apoptotic Effect of Respiratory Syncytial Virus on Human Peripheral Blood Neutrophils is Mediated by a Monocyte Derived Soluble Factor
No full textRespiratory Syncytial Virus (RSV) causes annual epidemics of respiratory disease particularly affecting infants. The associated airway inflammation is characterized by an intense neutrophilia. This neutrophilic inflammation appears to be responsible for much of the pathology and symptoms. Previous work from our group had shown that there are factors within the airways of infants with RSV bronchiolitis that inhibit neutrophil apoptosis. This study was undertaken to determine if RSV can directly affect neutrophil survival.NEUTROPHILS WERE ISOLATED FROM CITRATED VENOUS BLOOD (COLLECTED FROM HEALTHY ADULT VOLUNTEERS) BY DISCONTINUOUS PLASMA: Percoll gradient centrifugation and, in some experiments, further purified by negative immunomagnetic bead selection. The effect of RSV on neutrophil survival was measured by Annexin V-PE /To-Pro-3 staining and by morphological changes, using Dif-Quick staining of cytospins.Inhibition of neutrophil apoptosis was observed in neutrophils isolated by standard plasma:Percoll gradient when exposed to RSV but not in ultra pure neutrophil preparations. Adding monocytes back to ultra purified preparations restored the effect. The inhibition of apoptosis was observed with both active and UV inactivated virus. The effect is dependent on a soluble factor and appears to be dependent on CD14 receptors on the monocytes.</p
Pannexin 1 drives efficient epithelial repair after tissue injury
No full textEpithelial tissues such as lung and skin are exposed to the environment and therefore particularly vulnerable to damage during injury or infection. Rapid repair is therefore essential to restore function and organ homeostasis. Dysregulated epithelial tissue repair occurs in several human disease states, yet how individual cell types communicate and interact to coordinate tissue regeneration is incompletely understood. Here, we show that pannexin 1 (Panx1), a cell membrane channel activated by caspases in dying cells, drives efficient epithelial regeneration after tissue injury by regulating injury-induced epithelial proliferation. Lung airway epithelial injury promotes the Panx1-dependent release of factors including ATP, from dying epithelial cells which regulates macrophage phenotype post-injury. This process, in turn, induces a reparative response in tissue macrophages that includes the induction of the soluble mitogen amphiregulin, which promotes injury-induced epithelial proliferation. Analysis of regenerating lung epithelium identified Panx1-dependent induction of Nras and Bcas2, both of which positively promoted epithelial proliferation and tissue regeneration in vivo. We also established that this role of Panx1 in boosting epithelial repair after injury is conserved between mouse lung and zebrafish tailfin. These data identify a Panx1-mediated communication circuit between epithelial cells and macrophages as a key step in promoting epithelial regeneration post-injury
Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990.
No full textBACKGROUND: Intrapartum hypoxic events ("birth asphyxia") may result in stillbirth, neonatal or postneonatal mortality, and impairment. Systematic morbidity estimates for the burden of impairment outcomes are currently limited. Neonatal encephalopathy (NE) following an intrapartum hypoxic event is a strong predictor of long-term impairment. METHODS: Linear regression modeling was conducted on data identified through systematic reviews to estimate NE incidence and time trends for 184 countries. Meta-analyses were undertaken to estimate the risk of NE by sex of the newborn, neonatal case fatality rate, and impairment risk. A compartmental model estimated postneonatal survivors of NE, depending on access to care, and then the proportion of survivors with impairment. Separate modeling for the Global Burden of Disease 2010 (GBD2010) study estimated disability adjusted life years (DALYs), years of life with disability (YLDs), and years of life lost (YLLs) attributed to intrapartum-related events. RESULTS: In 2010, 1.15 million babies (uncertainty range: 0.89-1.60 million; 8.5 cases per 1,000 live births) were estimated to have developed NE associated with intrapartum events, with 96% born in low- and middle-income countries, as compared with 1.60 million in 1990 (11.7 cases per 1,000 live births). An estimated 287,000 (181,000-440,000) neonates with NE died in 2010; 233,000 (163,000-342,000) survived with moderate or severe neurodevelopmental impairment; and 181,000 (82,000-319,000) had mild impairment. In GBD2010, intrapartum-related conditions comprised 50.2 million DALYs (2.4% of total) and 6.1 million YLDs. CONCLUSION: Intrapartum-related conditions are a large global burden, mostly due to high mortality in low-income countries. Universal coverage of obstetric care and neonatal resuscitation would prevent most of these deaths and disabilities. Rates of impairment are highest in middle-income countries where neonatal intensive care was more recently introduced, but quality may be poor. In settings without neonatal intensive care, the impairment rate is low due to high mortality, which is relevant for the scale-up of basic neonatal resuscitation
Author Correction: Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity
No full textCorrection to: Nature Immunology https://doi.org/10.1038/s41590-025-02301-9, published online 28 October 2025.
In the version of this article initially published, the surname of Musa M. Mhlanga was misspelled (Mhalanga) and is now amended in the HTML and PDF versions of the article
Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation
No full textNeutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease
Glaucoma awareness
No full textThis thesis investigates three different aspects of glaucoma awareness
using both quantitative and qualitative methods.
Patient Awareness:
This qualitative study looked at patients perceptions of glaucoma.
Participants (N=28) reported low levels of awareness of glaucoma prior to
their diagnosis and assumed that symptoms were the ‘normal’
deterioration of eyesight. As symptoms have a gradual onset, participants
had learnt to cope with diminishing sight ability. Findings suggested
health promotion a priority to increase public awareness of the existence
and symptoms of glaucoma among those at high risk.
Current public awareness:
This study looked to document public awareness and knowledge of
glaucoma.
The study used health knowledge questionnaires in three different
populations:
1. nationally representative sample of 1009 people
2. telephone Interviews – 500 Isle of Wight, 226 Ealing
3. face-to-face interviews – 300 Ealing
Between 71-93% of those interviewed by telephone had heard of
glaucoma. However, only 23% of those interviewed face-to-face in Ealing
reported having heard of glaucoma. We found a relatively high level of awareness and knowledge of glaucoma in the general UK population but
identified at least one pocket of poor knowledge in a specific subpopulation.
Can we change awareness?
This study investigated whether a public health campaign could increase
awareness and change help-seeking behaviour with respect to ocular
health with residents in Southall, Ealing aged 60+. The health knowledge
questionnaire from the previous study was used to assess the campaign.
The health campaign comprised of four components.
1. Television
2. Local Press
3. Local Radio
4. Places of worship
The results showed a significant increase in the number of people who
had heard of Glaucoma rising from 22% to 53%. Before the intervention
most people had heard about glaucoma from their GP, friend or relative.
After intervention the majority (69%) had heard of glaucoma from the
radio.
This study showed a significant increase in awareness from using
different kinds of media and showed radio to be the most effective in the target community. Although the campaign raised awareness it did not
show a change in help seeking behaviour
Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses
No full textFully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease
Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity
No full textThe long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.</p
