Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?

The sequestration of Plasmodium falciparum–infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration

Effects of hyperbaric oxygen therapy on the viability of irradiated soft head and neck tissues in mice

Objectives Hyperbaric oxygen therapy (HBOT) is used clinically in irradiation-induced injury to healthy tissues, but the effectiveness and working mechanism remain unclear. This study examined the effects of HBOT on irradiated salivary glands and tongue in a mouse model. Materials and Methods Mice were irradiated with a single dose (15Gy) in the head and neck region and subjected to HBOT, either before or after irradiation. During the course of the treatments, salivary flow rates were measured and at different time points after radiation (2, 6, 10 and 24weeks), salivary glands and tongue were harvested and (immuno) histochemically analysed. Results Proliferation and blood vessel density in salivary glands were enhanced by HBOT in the medium term (10weeks after irradiation), while salivary flow rates were not influenced. In the long term, irradiation-induced proliferation in the muscle tissue of the tongue was decreased by HBOT. Conclusion Hyperbaric oxygen therapy (HBOT) appears to stimulate regeneration or protection of salivary gland tissue following radiation therapy. Possible implications of the effect of HBOT on muscle tissue of the tongue for the prevention of dysphagia and trismus are discussed. This study provides insights on the cellular changes after HBOT and encourages further research on this topic to achieve a better implementation of the therapy in humans

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGF beta-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

A side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT) is clinically used to treat radiation-induced damage but its mechanism of action is largely unknown. In this study, we investigated the molecular pathways that are affected by HBOT in mouse salivary glands two weeks after radiation therapy by microarray analysis. Interestingly, HBOT led to significant attenuation of the radiation-induced expression of a set of genes and upstream regulators that are involved in processes such as fibrosis and tissue regeneration. Our data suggest that the TGF beta-pathway, which is involved in radiation-induced fibrosis and chronic loss of function after radiation therapy, is affected by HBOT. On the longer term, HBOT reduced the expression of the fibrosis-associated factor alpha-smooth muscle actin in irradiated salivary glands. This study highlights the potential of HBOT to inhibit the TGF beta-pathway in irradiated salivary glands and to restrain consequential radiation induced tissue injury

Optical Imaging of Tumor Response to Hyperbaric Oxygen Treatment and Irradiation in an Orthotopic Mouse Model of Head and Neck Squamous Cell Carcinoma

Hyperbaric oxygen therapy (HBOT) is used in the treatment of radiation-induced tissue injury but its effect on (residual) tumor tissue is indistinct and therefore investigated in this study. Orthotopic FaDu tumors were established in mice, and the response of the (irradiated) tumors to HBOT was monitored by bioluminescence imaging. Near infrared fluorescence imaging using AngioSense750 and Hypoxisense680 was applied to detect tumor vascular permeability and hypoxia. HBOT treatment resulted in accelerated growth of non-irradiated tumors, but mouse survival was improved. Tumor vascular leakiness and hypoxia were enhanced after HBOT, whereas histological characteristics, epithelial-to-mesenchymal transition markers, and metastatic incidence were not influenced. Squamous cell carcinoma responds to HBOT with respect to tumor growth, vascular permeability, and hypoxia, which may have implications for its use in cancer patients. The ability to longitudinally analyze tumor characteristics highlights the versatility and potential of optical imaging methods in oncological research

Sequestration Properties of Blood Stages of <i>P. falciparum</i> in Humans and <i>P. berghei</i> ANKA in Rodents.

<p>Sequestration Properties of Blood Stages of <i>P. falciparum</i> in Humans and <i>P. berghei</i> ANKA in Rodents.</p

Imaging of transgenic <i>P. berghei</i> ANKA parasites in vivo and ex vivo.

<p>CD36-mediated sequestration of schizonts in adipose tissue and lungs (adapted from PNAS, 2005 <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001032#ppat.1001032-FrankeFayard1" target="_blank">[35]</a>). (A, B) Distribution of transgenic <i>P. berghei</i> ANKA parasites, expressing GFP::luciferase fusion protein (<i>ama-1</i> promoter, see <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001032#ppat-1001032-box003" target="_blank">Box 3</a>). Parasites are visible in lungs, spleen, and adipose tissue in wild-type mice, and principally in the blood circulation and accumulated in the spleen in CD36 knock-out mice. In wild-type mice infected with a non-sequestering K173 line, schizonts are also mainly found in the peripheral blood circulation and accumulated in the spleen (1: adipose tissue; 2: spleen; 3 liver; 4: lungs; 5: heart; 6: kidney; 7: brain). (C) Sequestration of transgenic <i>P. berghei</i> ANKA parasites in microvasculature of adipose tissue (upper panel with under phase contrast and lower panel with GFP-positive schizonts indicated by arrows).</p