Dataset Information

Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs.

ABSTRACT:

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The molecular networks underlying the lung response to hypoxia are not fully understood. We employed systems biology approaches to study temporal effects of intermittent or sustained hypoxia on gene expression in rat lungs. We obtained gene expression profiles from rats exposed to intermittent or sustained hypoxia lasting 0-30 days and identified differentially expressed genes, their patterns, biological processes, and regulatory networks critical for lung response to intermittent or sustained hypoxia. We validated selected genes with quantitative real-time PCR. Intermittent and sustained hypoxia induced two distinct sets of genes in rat lungs that displayed different temporal expression patterns. Intermittent hypoxia induced genes mostly involved in ion transport and homeostasis, neurological processes, and steroid hormone receptor activity, while sustained hypoxia induced genes principally participating in immune responses. The intermittent hypoxia-activated network suggested a role for cross talk between estrogen receptor 1 (ESR1) and other key proteins in hypoxic responses. The sustained hypoxia-activated network was indicative of vascular remodeling and pulmonary hypertension. We confirmed the temporal expression changes of 12 genes (including the Esr1 gene and 4 ESR1 target genes) in intermittent hypoxia and 8 genes in sustained hypoxia with quantitative real-time PCR.

Conclusions

intermittent and sustained hypoxia induced distinct gene expression patterns in rat lungs. The functional characteristics of genes activated by these two distinct perturbations suggest their roles in the downstream physiological effects of intermittent and sustained hypoxia. Our results demonstrate the discovery potential of applying systems biology approaches to the understanding of mechanisms underlying hypoxic lung response.

SUBMITTER: Wu W

PROVIDER: S-EPMC2604785 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs.

Wu Wei W Dave Nilesh B NB Yu Guoying G Strollo Patrick J PJ Kovkarova-Naumovski Elizabeta E Ryter Stefan W SW Reeves Stephen R SR Dayyat Ehab E Wang Yang Y Choi Augustine M K AM Gozal David D Kaminski Naftali N

Physiological genomics 20080930 1

<h4>Unlabelled</h4>The molecular networks underlying the lung response to hypoxia are not fully understood. We employed systems biology approaches to study temporal effects of intermittent or sustained hypoxia on gene expression in rat lungs. We obtained gene expression profiles from rats exposed to intermittent or sustained hypoxia lasting 0-30 days and identified differentially expressed genes, their patterns, biological processes, and regulatory networks critical for lung response to intermit ...[more]

PMID: 18826996

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Project description:Venous thromboembolism (VTE) is a leading cause of preventable deaths in hospitals, and its incidence is not decreasing despite extensive efforts in clinical and laboratory research. Venous thrombi are primarily formed in the valve pockets of deep veins, where activated monocytes play a crucial role in bridging innate immune activation and hemostatic pathways through the production of inflammatory cytokines, chemokines, and tissue factor (TF) - a principal initiator of coagulation. In the valve pocket inflammation and hypoxia (sustained/intermittent) coexist, however their combined effects on immunothrombotic processes are poorly understood. Inflammation is strongly associated with VTE, while the additional contribution of hypoxia remains largely unexplored. To investigate this, we modelled the intricate conditions of the venous valve pocket using a state-of-the-art hypoxia chamber with software-controlled oxygen cycling. We comprehensively studied the effects of sustained and intermittent hypoxia alone, and in combination with VTE-associated inflammatory stimuli on primary monocytes. TF expression and activity was measured in monocytes subjected to sustained and intermittent hypoxia alone, or in combination with IL-1β. Monocyte responses were further analyzed in detailed by RNA sequencing and validated by ELISA. Stimulation with IL-1β alone promoted both transcription and activity of TF. Interestingly, the stimulatory effect of IL-1β on TF was attenuated by sustained hypoxia, but not by intermittent hypoxia. Our transcriptome analysis further confirmed that sustained hypoxia limited the pro-inflammatory response induced by IL-1β, and triggered a metabolic shift in monocytes. Intermittent hypoxia alone had a modest effect on monocyte transcript. However, in combination with IL-1β intermittent hypoxia significantly altered the expression of 2207 genes and enhanced the IL-1β-stimulatory effects on several chemokine and interleukin genes (e.g., IL-19, IL-24, IL-32, MIF), as well as genes involved in coagulation (thrombomodulin) and fibrinolysis (VEGFA, MMP9, MMP14 and PAI-1). Increased production of CCL2, IL-6 and TNF following stimulation with intermittent hypoxia and IL-1β was confirmed by ELISA. Our findings provide valuable insights into how the different hypoxic profiles shape the immunothrombotic response of monocytes and shed new light on the early events in the pathogenesis of venous thrombosis.

Dataset Information

Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs.

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Conclusions

Publications

Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs.

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