We recently submitted an abstract for the annual Radiation Research Society meeting. This year it is in Maui. I’m not sure if I’ll have the money to go or not but several of us at the lab are planning to attend. Worst case, I may send my poster with one of them.  The work for this abstract was done almost exclusively by my tech, Erben Bayeta, and our summer student Cory Pan.  Cory is planning on returning to our lab this summer to do some follow up studies.  I’m sure we have more than enough to keep him busy.    Celso Perez has joined us to start doing some work in his spare time (he’s actually our lab manager).  He should have some data on a third cell line by the time the symposium comes around.  I’ve attached some of the data we are presenting to this post.

Anyway, here’s the abstract:

Does ethyl pyruvate act as a radioprotectant in macrophage cell lines?

Michael J. Pecaut^1,2, Erben Bayeta¹, Cory Pan³, Celso P. Perez¹, Daila S. Gridley^1,2

Depts. of ¹Radiation Medicine (Radiation Research Laboratories), ²Basic Sciences, and ³Center for Health Disparities and Molecular Medicine, Loma Linda University & Medical Center, Loma Linda, CA 92354.

Exposure to radiation is known to cause inflammation, a process that sometimes leads to complications in patients undergoing radiotherapy. Ethyl Pyruvate (EP) has proven to be an effective countermeasure against damage incurred during sepsis, ischemia/reperfusion injury, and hemorrhagic shock.  Because of its anti-inflammatory properties, this low molecular weight compound is being considered as a potential radioprotectant.  Indeed, preliminary work by others indicates that EP can impact measures of apoptosis in vitro and increases survival in mice after whole-body irradiation (Epperly, et al, Radiation Research 168:552-559, 2007). With this in mind, we characterized the efficacy of EP in mitigating the effects of radiation on several measures of oxidative stress in macrophage cell lines (including RAW264.7 & J774.A1).  Cells were treated with 0-10 mM EP for 60 minutes and subsequently exposed to 0-4 Gy g-irradiation (⁶⁰Co) in a single fraction at a dose rate of 0.8 Gy/min.  After a 24 hour incubation period, we assessed cell survival, background reactive oxygen species (ROS) levels, oxidative burst capacity, total protein and glutathione (GSH) levels.  Each experiment was repeated five times to ensure repeatability.  Data from all five experiments were normalized to controls and combined for the final analysis.  Although we found very reliable main effects of both radiation and EP (P<0.001 for most endpoints), there were no significant radiation x EP interactions on any characterized parameter.  This would seem to indicate the protective nature of EP does not directly involve changes in reactive oxygen metabolism within macrophages.

“LORA M. GREEN PhD Untouched Serenity Offsetting the intense sorrow of her loss on January 11, 2010, as colleagues, friends and family we have had the joy of working, relaxing and living with Lora–husband of 35 years, Timothy Green and son, Keigm Green; daughter of Marlene and Everett (deceased) Murray. In her Redlands, CA home, Lora was diverse in her interests in people, ideas and actions — a researcher, artist, mentor, comedian, teacher, gambler, and “five-star scientist.” But above the science, her humble way, enthusiasm, humor and goodness depicts Lora’s unique and beautiful being.”

Spaceflight Modulates Expression of Extracellular Matrix, Adhesion and Profibrotic Molecules in Mouse Lung.

Tian J, Pecaut MJ, Slater JM, Gridley DS.

NASA has reported pulmonary abnormalities in astronauts on space missions, but the molecular changes in lung tissue remain unknown. The goal of the present study was to explore the effects of spaceflight on expression of extracellular matrix (ECM), cell adhesion and pro-fibrotic molecules in lungs of mice flown on Space Shuttle Endeavour (STS-118). C57BL/6Ntac mice housed in animal enclosure modules during a 13-day mission in space (FLT) were euthanized within hours after return; ground controls were treated similarly for comparison (GRD). Analysis of genes associated with ECM and adhesion molecules was performed according to quantitative RT-PCR. The data revealed that FLT lung samples had statistically significant transcriptional changes, i.e., at least 1.5-fold, in 25 out of 84 examined genes (P < 0.05); 15 genes were up-regulated and 10 were down-regulated. The genes that were up-regulated by more than 2-fold were Ctgf, Mmp2, Ncam1, Sparc, Spock1, and Timp3, whereas the most down-regulated genes were Lama1, Mmp3, Mmp7, vcam-1, and Sele. Histology showed profibrosis-like changes occurred in FLT mice, more abundant collagen accumulation around blood vessels, and thicker walls compared with lung samples form GRD mice. Immunohistochemistry was used to compare expression of six selected proteins associated with fibrosis. Immunoreactivity of four proteins (MMP-2, CTGF, TGF-beta1, and NCAM) was enhanced by spaceflight, whereas, no difference was detected in expression of MMP-7 and MMP-9 proteins between the FLT and GRD groups. Taken together, the data demonstrate that significant changes can be readily detected shortly after return from spaceflight in the expression of factors that can adversely influence lung function. Key words: space shuttle, respiratory tract, gene expression, histopathology.

Jack’s been very productive this year. Believe it or not, he already has a third paper on the way and we’re about to send it out for review. We also have papers in review by Asma Rizvi (LLU), Ty Lebsack (ASU), and myself. Two of those have already been accepted with minor revisions, too, so we expect to see them in publication within the next couple of months.

Farnaz Baqai spent the summer studying for her MCATs, but she is back in the lab working hard on finishing up some of her immunohistochemistry. She has at least two papers worth of data from her dissertation and, hopefully, she’ll be able to write that data up in the next few months as well.

Erben Bayeta has been working on several in vitro studies using our macrophage cell lines. So far, we’ve repeated a number of dose response studies (testing the efficacy of ethyl pyruvate as a radioprotectant). Short version, we aren’t seeing much of a protective effect on oxidative burst capacity. In fact, it seems to be a bit toxic to our macrophages at higher concentrations. However, we’re not sure if it’s really killing the cells or slowing down replication. We’re working on teasing that out.

There have been a couple of conferences in the last month. In October, Farnaz and I went to the annual Radiation Research Society meeting in Savannah, Georgia. Farnaz had a poster and was invited to give a short talk describing her work (including a travel grant award). I was also invited out to give a short overview of spaceflight immune data for a seminar run by Ted Bateman and Greg Nelson.

More recently, I attended the annual meeting for the American Society for Gravitational and Space Biology. I wasn’t originally planning on attending this meeting even though it’s one of my favorites. I just didn’t have the money to go. However, Keith Chapes told me I needed to be there for a “round-table discussion about spaceflight.” So, Daila Gridley managed to scrounge up some funds and I was able to go. Turns out, there was no discussion. This was just a ruse (one which Daila was in on). Instead, they had nominated me to receive the “Thora W. Halstead Young Investigator Award.” Since I won, I kinda had to go. Haha. It’s an honor to win the award, but that was downright sneaky! Haha.

Last, but not least, I recently submitted another grant to NIH for the NIH/NASA ISS FOA.  Here’s the abstract for that.

According to the National Institute of Health, “There are approximately 35 million Americans age 65 or older, and this number is expected to double in the next 25 years.” Consequently, there is a rapidly growing need to understand the mechanisms underlying age-associated illness. Evidence that suggests that many of the diseases associated with aging are also associated with dysregulation in immune responses and pro-inflammatory mediators. Age-associated deficits are likely linked to dynamic interactions between reactive oxygen species (ROS) and inflammatory cytokines. Prolonged exposure to the spaceflight environment results in many of the same deficits usually associated with aging, such as osteoporosis, muscle atrophy, and immune dysfunction. The International Space Station provides an ideal laboratory within which investigators can explore this unique environment. By characterizing these deficits in otherwise healthy human astronauts, we believe we will be able to establish a causal link between ROS metabolism and age-dependent immune dysfunction, clearing the way for the development of new treatments and techniques.

I guess that’s it!

Cory Pan

Does Ethyl Pyruvate Protect Macrophages from Gamma Radiation Damage?

Background: In the last ten years, the threat of radiation exposure due to terrorist attacks (e.g. so called “dirty bombs”) or nuclear weaponry (e.g. by North Korea or Iran) has increased significantly. Similarly, exposure to radiation during space flight is also becoming a growing concern for astronauts, particularly with the increased emphasis on manned Lunar and Mars exploration. Outside the protective terrestrial atmosphere and geomagnetic field, astronauts will be exposed to radiation via Galactic Cosmic Rays (GCRs) and Solar Particle Events (SPEs). Considering the lengthy amount of exposure to radiation, and the numerous effects the radiation has on the human body, it is important to find new protective agents that will protect our immune system. Radiation is known to increase the amount of reactive oxygen species (ROS) in tissues. ROS are a byproduct of normal metabolism and are important in cell communication. However, excessive amounts of ROS can lead to tissue damage. In previous in vivo experiment models, EP had no detectable radioprotective or mitigating effects but it is suggested that EP might be an effective radioprotector and mitigator of the hematopietic syndrome induced by TBI (Epperl, 2008).

Macrophages are essential to our immune system because they are among the first cells to respond to an immune challenge.  They not only devour potential pathogens, but they also present antigens to immunocytes involved in cell mediated immunity. ROS are particularly important in macrophage pathogen elimination because they contain small molecules such as free radicals that destroy pathogens.

This study focuses on the protective properties of the drug ethyl  pyruvate (EP) on macrophages. In past studies, ethyl pyruvate, a simple aliphatic ester of pyruvic acid, has been shown to have anti-inflammatory effects in numerous cell culture and animal studies such as intestinal inflammatory response and neuroprotection in the brain. Similarly, radiation-induced tissue damage has also been linked to inflammatory mechanisms.  Given that radiation is known to induce cancerous growth and that EP is known to reduce inflammatory responses, we hypothesized that EP would act as a radioprotective agent.  Given that macrophages are a major component of immune defense, we believed that EP will have a profound radioprotective affect in this population.

Effects of Radiation and Ethyl Pyruvate on Macrophage Oxidative Function. All values represent Mean ± SEM. § ANOVA: Main effect of Radiation (P<0.001), Main effect of Ethyl Pyruvate (P<0.001).

Conclusion: There was significant radiation (P<0.001) and ethyl pyruvate (P<0.001) effects on all quantified parameters.  In contrast, there were no significant interactions between radiation exposure and ethyl pyruvate treatment.  This suggests that ethyl pyruvate does not protect macrophages against radiation for our endpoints.  However, we can not rule out that EP alters radiation-induced cytokine expression. Previous studies have shown, a increase in EP concentration decreased the amount of TNF-a and IL-6, inflammatory cytokines, available (Marieke 2007). Therefore, we will look into the effect of ethyl pyruvate on cytokine as our next study.

Most importantly, Farnaz graduated.  Yeah, team!  Her oral defense went well, despite her butterflies and the committee was impressed.  She’s off studying for her MCAT over the summer, but she promises me that she’ll come back in the fall and convert two chapters of her dissertation into two manuscripts.  She better because she put a ton of work into those studies and dataz must be published!  Heh.  She was also awarded a travel grant for the upcoming Radiation Research Meeting in Savannah, Georgia.  In fact, they selected her abstract for an oral presentation so they must have thought she did something worth hearing.

Although I am not officially a member of the Radiation Research Society (my work tends to be more spaceflight oriented than clinical), I will be joining her in Savannah.  I was asked to give a short overview of spaceflight effects on immunity.  I’ll probably be sandwiched between talks about space psychology and space osteoimmunology.

We’re also working on submitting a few more radiation manuscripts.  One will be some old data from BNL that we are finally getting around to publish.  This study looked at the effects of iron radiation on immune parameters in two different strains of mice (C57BL/6 and CBA/Ca) and at two different time points (Day 4 vs Day 30).  We found some rather interesting strain x radiation interactions on liver mass that looked remarkably similar to changes in RBC/hemoglobin levels.  The second paper is based on some old behavior data from our former student, Cara Zuccarelli.  She looked at the effects of gamma and proton radiation on the acoustic startle response.  And lastly, we are working on another set of data from our last space shuttle experiment.  This time we are reporting on spaceflight effects on lung; specifically on changes in the extracellular matrix.  We are hoping that all three papers will be accepted by the end of summer.  Cross your fingers.

As for grant proposals, I am currently working on rewriting an NIH proposal that is due on July 16th.  We are proposing that the long term behavioral deficits seen in hematopoietic stem cell transplant patients are partially due to radiation-induced inflammation.  We hope that once we have found the mechanisms behind these deficits, we will be in a strong position to develop immune-based countermesures (e.g. cytokine management).

Earlier this year, I collaborated with Ted Bateman at Clemson on another proposal in response to Obama’s Challenge Grant RFP.  That one was a radiation and osteoimmune proposal, focusing on NADPH oxidase and reactive oxygen.  It makes sense for our lab because osteoclasts are basically tissue specific macrophages.  It should be interesting work if we get funding.  Wish us luck!

Last but not least, we have a summer high school student working with us.  His name is Cory Pan and he’s looking at the effects of radiation on one of our macrophage cell lines.  Specifically, he is looking at gamma radiation-induced changes in background and induced ROS expression.  If he gets through that in time, we’re planning on looking at phagocytosis as well.  He seems pretty enthusiastic and, theoretically, is learning from his frequent mistakes.  Hahaha.  At some point, I’ll put up a link with more info on the left side of this page.

I guess that’s it.  One of these days we’ll have to start throwing data onto this page for comments.  But that requires that I get my act together.  Ha.

Ironically (or coincidentally, I haven’t decided which), we received the acceptance letter from JAP for our third immune publication from the last shuttle flight on the same day.  The reviewers were pretty rough on us, though.  It bounced back and forth three times before they finally accepted it. Farnaz was pretty excited as this was her first publication.  Woot! Now all she has to do is finish her dissertation and graduate.  Hahaha.  It’s still an Epub ahead of print, so I don’t have a reprint.  Give it a few weeks. For now, here’s the abstract.

Effects of spaceflight on innate immune function and antioxidant gene expression.

Baqai FP, Gridley DS, Slater JM, Luo-Owen X, Stodieck LS, Ferguson VL, Chapes SK, Pecaut MJ.

Spaceflight conditions have a significant impact on a number of physiological functions due to psychological stress, radiation and reduced gravity. To explore the effect of the flight environment on immunity, C57BL/6NTac mice were flown on a 13-day space shuttle mission (STS-118). In response to flight, animals had a reduction in liver, spleen and thymus masses compared to ground (GRD) controls (p<0.005). Splenic lymphocytes, monocyte/macrophages and granulocyte counts were significantly reduced in the flight (FLT) mice (p<0.05). Although spontaneous blastogenesis of splenocytes in FLT mice was increased, response to lipopolysaccharide (LPS), a B cell mitogen derived from E. coli, was decreased compared to GRD mice (p<0.05). Secretion of IL-6 and IL-10, but not that of TNF-alpha by LPS-stimulated splenocytes was increased in FLT mice (p<0.05). Finally, many of the genes responsible for scavenging ROS were up-regulated after flight. These data indicate that exposure to the spaceflight environment can increase anti-inflammatory mechanisms and change the ex vivo response to lipopolysaccharide (LPS), a bacterial product associated with septic shock and a prominent Th1 response.

Daila also had two additional publications.  One on protons and one on photons, but both T cell gene expression.  Here are those abstracts.

Low Dose, Low Dose Rate Photon Radiation Modifies Leukocyte Distribution and Gene Expression in CD4(+) T Cells.

Gridley DS, Rizvi A, Luo-Owen X, Makinde AY, Pecaut MJ.

A better understanding of low dose radiation effects is needed to accurately estimate health risks. In this study, C57BL/6 mice were gamma-irradiated to total doses of 0, 0.01, 0.05, and 0.1 Gy ((57)Co; ~0.02 cGy/h). Subsets per group were euthanized at the end of irradiation (day 0) and on days 4 and 21 thereafter. Relative spleen mass and splenic white blood cell (WBC) counts, major leukocyte populations, and spontaneous DNA synthesis were consistently higher in the irradiated groups on day 0 compared to 0 Gy controls, although significance was not always obtained. In the spleen, all three major leukocyte types were significantly elevated on day 0 (P < 0.05). By day 21 post-irradiation the T, B, and natural killer (NK) cell counts, as well as CD4(+) T cells and CD4:CD8 T cell ratio, were low especially in the 0.01 Gy group. Although blood analyses showed no significant differences in leukocyte counts or red blood cell and platelet characteristics, the total T cells, CD4(+) T cells, and NK cells were increased by day 21 after 0.01 Gy (P < 0.05). Gene analysis of CD4(+) T cells negatively isolated from spleens on day 0 after 0.1 Gy showed significantly enhanced expression of Il27 and Tcfcp2, whereas Inha and Socs5 were down-regulated by 0.01 Gy and 0.1 Gy, respectively (P < 0.05). A trend for enhancement was noted in two additional genes (Il1r1 and Tbx21) in the 0.1 Gy group (P < 0.1). The data show that protracted low dose photons had dose- and time-dependent effects on CD4(+) T cells after whole-body exposure.

Low-dose, low-dose-rate proton radiation modulates CD4(+) T cell gene expression.

Gridley DS, Pecaut MJ, Rizvi A, Coutrakon GB, Luo-Owen X, Makinde AY, Slater JM.

Purpose: To evaluate cluster of differentiation 4(+) (CD4(+)) T cell gene expression and related parameters after whole-body exposure to proton radiation as it occurs in the spaceflight environment. Materials and methods: C57BL/6 mice were irradiated to total doses of 0, 0.01, 0.05, and 0.1 gray (Gy) at 0.1 cGy/h. On day 0 spleens were harvested from a subset in the 0, 0.01 and 0.1 Gy groups; (CD4(+)) T cells were isolated; and expression of 84 genes relevant to T helper (Th) cell function was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). Remaining mice were euthanized on days 0, 4, and 21 for additional analyses. Results: Genes with >2-fold difference and p < 0.05 compared to 0 Gy were noted. After 0.01 Gy, five genes were up-regulated (Ccr5, Cd40, Cebpb, Igsf6, Tnfsf4) and three were down-regulated (Il4ra, Mapk8, Nfkb1). After 0.1 Gy there were nine up-regulated genes (Ccr4, Cd40, Cebpb, Cxcr3, Socs5, Stat4, Tbx21, Tnfrsf4, Tnfsf4); none were down-regulated. On day 0 after 0.01 Gy, CD4(+) T cell counts and CD4:CD8 ratio were low in the spleen (p < 0.05). Spontaneous DNA synthesis in both spleen and blood was lowest in the 0.01 Gy group on day 0; on days 4 and 21 all p values were >0.1. Conclusion: The data show that the pattern of gene expression in CD4(+) T cells after protracted low-dose proton irradiation was significantly modified and highly dependent upon total dose. The findings also suggest that low-dose radiation, especially 0.01 Gy, may enhance CD4(+) T cell responsiveness.

First, the bad news.  Both NIH and DOE have turned down my grant proposals.  I will probably try to resubmit the NIH grant this summer once I figure out how to address some of the reviewer concerns.  I gotta keep remembering that being a scientist requires a thick skin and a short memory when it comes to rejection.  Good thing I’m showing signs of early onset Alzheimer’s.  Hah!

I still haven’t heard back from NASA regarding my Mice In Space proposal.  I’m not sure what is holding it up.  My guess is the recent economic issues have made spaceflight an even more difficult prospect than usual.  Plus, they may be trying to work out a way to blend two or more proposals together.  Given the lack of funds for science in general, this is probably harder than it sounds.

We also haven’t heard from LLU regarding our NMTB grant proposal.  Seems LLU got a lot more proposals than they expected and they are having a harder time deciding who gets what.  They may also be debating cutting the funding cap in order to fund more individual projects.  I have no idea.

On to the good news.  Farnaz had or Oral Defense a few weeks ago.  We invited my mentor from CU, Monika Fleshner, to sit on her committee along with several investigators from LLU including Penelope Duerksen-Hughes, Denise Bellinger, and Daila Gridley.  With all those smart people in the room, I think I was at least as nervous as Farnaz.  Hah.  It was pretty grueling, as you might expect, but she passed.  Now she’s in the process of analyzing the rest of her data and addressing the committee concerns.

Also, our publication list keeps growing.  One of these days I’ll have to update our publications page.  For now, here are the abstracts from PubMed to latest few.  They include immune, bone, radiation and spaceflight related data.  They also demonstrate our continued collaborations with Ted Bateman at Clemson University, Keith Chapes at Kansas State, as well as Louis Stodieck and Ginger Ferguson at the University of Colorado at Boulder:

Radiation and secondary immune response to lipopolysaccharide.

Pecaut MJ, Gridley DS.

BACKGROUND: The purpose of this study was to determine whether secondary immune responses to lipopolysaccharide (LPS) were altered by exposure to radiation. MATERIALS AND METHODS: C57BL/6 mice were irradiated (60Co, gamma-rays) to 0 or 3 Gray (Gy) and injected intraperitoneally with LPS on days 10 and 42 thereafter. Subsets were euthanized 0-14 days after the second injection for analyses. RESULTS: The data show numerous radiation-induced effects, as well as some significant interactions among radiation, LPS, and day of analysis. Among the most striking were changes in thymus mass, circulating lymphocytes, monocytes, granulocytes, and specific lymphocyte subpopulations, erythrocyte counts, hematocrit, and platelet counts and volume. Spontaneous blastogenesis and oxidative burst capacity of phagocytic cells, however, were relatively normal. CONCLUSION: The findings indicate that exposure to radiation at a spaceflight relevant dose can influence the distribution of certain leukocyte populations in response to a secondary challenge with LPS.

Spaceflight effects on T lymphocyte distribution, function and gene expression.

Gridley DS, Slater JM, Luo-Owen X, Rizvi A, Chapes SK, Stodieck LS, Ferguson VL, Pecaut MJ.

The immune system is highly sensitive to stressors present during spaceflight. The major emphasis of this study was on the T lymphocytes in C57BL/6NTac mice after return from a 13-day space shuttle mission (STS-118). Spleens and thymuses from flight animals (FLT) and ground controls similarly housed in animal enclosure modules (AEM) were evaluated within 3-6 h after landing. Phytohemagglutinin-induced splenocyte DNA synthesis was significantly reduced in FLT mice when based on both counts per minute and stimulation indexes (P < 0.05). Flow cytometry showed that CD3(+) T and CD19(+) B cell counts were low in spleens from the FLT group, whereas the number of NK1.1(+) natural killer (NK) cells was increased (P < 0.01 for all three populations vs. AEM). The numerical changes resulted in a low percentage of T cells and high percentage of NK cells in FLT animals (P < 0.05). After activation of spleen cells with anti-CD3 monoclonal antibody, interleukin-2 (IL-2) was decreased, but IL-10, interferon-gamma, and macrophage inflammatory protein-1alpha were increased in FLT mice (P < 0.05). Analysis of cancer-related genes in the thymus showed that the expression of 30 of 84 genes was significantly affected by flight (P < 0.05). Genes that differed from AEM controls by at least 1.5-fold were Birc5, Figf, Grb2, and Tert (upregulated) and Fos, Ifnb1, Itgb3, Mmp9, Myc, Pdgfb, S100a4, Thbs, and Tnf (downregulated). Collectively, the data show that T cell distribution, function, and gene expression are significantly modified shortly after return from the spaceflight environment.

Shifts in bone marrow cell phenotypes caused by spaceflight.

Ortega MT, Pecaut MJ, Gridley DS, Stodieck LS, Ferguson V, Chapes SK.

Bone marrow cells were isolated from the humeri of C57BL/6 mice after a 13-day flight on the space shuttle Space Transportation System (STS)-118 to determine how spaceflight affects differentiation of cells in the granulocytic lineage. We used flow cytometry to assess the expression of molecules that define the maturation/activation state of cells in the granulocytic lineage on three bone marrow cell subpopulations. These molecules included Ly6C, CD11b, CD31 (platelet endothelial cell adhesion molecule-1), Ly6G (Gr-1), F4/80, CD44, and c-Fos. The three subpopulations were small agranular cells [region (R)1], larger granular cells (R2), which were mostly neutrophils, and very large, very granular cells (R3), which had properties of macrophages. Although there were no composite phenotypic differences between total bone marrow cells isolated from spaceflight and ground-control mice, there were subpopulation differences in Ly6C (R1 and R3), CD11b (R2), CD31 (R1, R2, and R3), Ly6G (R3), F4/80 (R3), CD44(high) (R3), and c-Fos (R1, R2, and R3). In particular, the elevation of CD11b in the R2 subpopulation suggests neutrophil activation in response to landing. In addition, decreases in Ly6C, c-Fos, CD44(high), and Ly6G and an increase in F4/80 suggest that the cells in the bone marrow R3 subpopulation of spaceflight mice were more differentiated compared with ground-control mice. The presence of more differentiated cells may not pose an immediate risk to immune resistance. However, the reduction in less differentiated cells may forebode future consequences for macrophage production and host defenses. This is of particular importance to considerations of future long-term spaceflights.

Spaceflight-relevant types of ionizing radiation and cortical bone: Potential LET effect?

Lloyd SA, Bandstra ER, Travis ND, Nelson GA, Bourland JD, Pecaut MJ, Gridley DS, Willey JS, Bateman TA.

Extended exposure to microgravity conditions results in significant bone loss. Coupled with radiation exposure, this phenomenon may place astronauts at a greater risk for mission-critical fractures. In a previous study, we identified a profound and prolonged loss of trabecular bone (29-39%) in mice following exposure to an acute, 2 Gy dose of radiation simulating both solar and cosmic sources. However, because skeletal strength depends on trabecular and cortical bone, accurate assessment of strength requires analysis of both bone compartments. The objective of the present study was to examine various properties of cortical bone in mice following exposure to multiple types of spaceflight-relevant radiation. Nine-week old, female C57BL/6 mice were sacrificed 110 days after exposure to a single, whole body, 2 Gy dose of gamma, proton, carbon, or iron radiation. Femora were evaluated with biomechanical testing, microcomputed tomography, quantitative histomorphometry, percent mineral content, and micro-hardness analysis. Compared to non-irradiated controls, there were significant differences compared to carbon or iron radiation for only fracture force, medullary area and mineral content. A greater differential effect based on linear energy transfer (LET) level may be present: high-LET (carbon or iron) particle irradiation was associated with a decline in structural properties (maximum force, fracture force, medullary area, and cortical porosity) and mineral composition compared to low-LET radiation (gamma and proton). Bone loss following irradiation appears to be largely specific to trabecular bone and may indicate unique biological microenvironments and microdosimetry conditions. However, the limited time points examined and non-haversian skeletal structure of the mice employed highlight the need for further investigation.

I suppose that’s it for now.  We have a couple more publications already in review (including at least one more spaceflight & immune paper) and we are preparing several more for submission.

“A short, satirical video produced by an astronaut and posted on YouTube is generating a lot of discussion within NASA and the space community. The video focuses on making sure the agency’s bureaucracy doesn’t crush innovative ideas and dissenting opinions.”

It’s been a running joke in some circles that once you start to work for NASA, you move away from doing actual science and start slipping into a management black hole.  A lot of the research NASA depends on is actually done outside of the organization and in the University setting.  Much like the work in our lab.  As I’ve seen both the science and the engineering sides of NASA, some of this sounds all too real.  I’m glad to hear that NASA is taking this criticism seriously.

The news for our NIH proposal is less good.  In this proposal we were focusing on the low dose radiation patients receive for bone marrow transplants and the long term immune and behavioral consequences. Unfortunately, the proposal was returned without a score.  We’re still waiting on the review.