Exertional heat injury and gene expression changes: a DNA microarray analysis study

Abstract

This study examined gene expression changes associated with exertional heat injury (EHI) in vivo and compared these changes to in vitro heat shock responses previously reported by our laboratory. Peripheral blood mononuclear cell (PBMC) RNA was obtained from four male Marine recruits (ages 17-19 yr) who presented with symptoms consistent with EHI, core temperatures ranging from 39.3 to 42.5 degrees C, and elevations in serum enzymes such as creatine kinase. Controls were age- and gender-matched Marines from whom samples were obtained before and several days after an intense field-training exercise in the heat ("The Crucible"). Expression analysis was performed on Affymetrix arrays (containing approximately 12,600 sequences) from pooled samples obtained at three times for EHI group (at presentation, 2-3 h after cooling, and 1-2 days later) and compared with control values (average signals from two chips representing pre- and post-Crucible samples). After post hoc filtering, the analysis identified 361 transcripts that had twofold or greater increases in expression at one or more of the time points assayed and 331 transcripts that had twofold or greater decreases in expression. The affected transcripts included sequences previously shown to be heat-shock responsive in PBMCs in vitro (including both heat shock proteins and non-heat shock proteins), a number of sequences whose changes in expression had not previously been noted as a result of in vitro heat shock in PBMCs (including several interferon-induced sequences), and several nonspecific stress response genes (including ubiquitin C and dual-specificity phosphatase-1). We conclude that EHI produces a broad stress response that is detectable in PBMCs and that heat stress per se can only account for some of the observed changes in transcript expression. The molecular evidence from these patients is thus consistent with the hypothesis that EHI can result from cumulative effects of multiple adverse interacting stimuli.

Core temperature correlates with expression of selected stress and immunomodulatory genes in febrile patients with sepsis and noninfectious SIRS

“…Those which showed increased expression with increasing temperature included several heat shock proteins (including HSP 110, several members of the DNAJ family of HSPs, HSP 56, and HSP 27-1), superoxide dismutase-1, cell adhesion molecules (including ICAM-1/ CD54, CD11b, and JAM3), heat shock transcription factors HSF-1 and HSF-4, and several molecules involved in immune function, such as CXCL5 and -7. Sequences whose expression (1) Correlation coefficient and correlation P computed by Spearman's rho; (2) previously reported to show increased expression after exertional heat injury (Sonna et al 2004); (3) also increased after exertional heat injury (Sonna et al 2004;previously unpublished finding) decreased with increasing temperature included Toll-like receptors TLR-6 and TLR-7, CD47, T-cell differentiation protein MAL, a handful of HSPs/chaperonins, and several ribosomal proteins. Several of the sequences whose expression correlated with temperature in this study have previously been shown to be affected by exertional heat injury (EHI) in PBMCs (Sonna et al 2004).…”

“…These sequences are summarized in Table 4. To better identify the nature of these interactive effects, we performed a correlation analysis of temperature and gene (1) Correlation coefficient and correlation P computed by Spearman's rho; (2) previously reported to show decreased expression after exertional heat injury (Sonna et al 2004); (3) also decreased after exertional heat injury (Sonna et al 2004; previously unpublished finding); (4) previously reported to show increased expression after exertional heat injury (Sonna et al 2004) expression signal for each of these genes, stratified by clinical diagnosis. Correlation analysis was performed using two-tailed Pearson's analysis unless otherwise specified.…”

“…Effect on control sequences Table 6 shows the effect of temperature and clinical condition on the expression of sequences corresponding to genes that have previously been reported to display stable expression over time in peripheral blood mononuclear cells obtained from individuals EHI (Sonna et al 2004). There was no statistically significant effect of temperature or clinical condition on the expression of these control sequences.…”

“…Clinically, some of the changes that characterize the heat shock response in vitro have been detected in individuals who suffered exertional heat injury (Sonna et al 2004). However, there is evidence to suggest that, even in healthy individuals, modest elevations in body temperature might cause changes in gene expression as well.…”

Image-guided genomic analysis of tissue response to laser-induced thermal stress

“…Although genes encoding hsps have been well studied, thermal stress leads to increased expression of a substantial number of genes not normally considered to be hsps. 19,20 These genes can be affected by a variety of different stressors and therefore represent a nonspecific cellular response to stress. Analysis of the inactivation of keratinocytes from short exposure (on the order of seconds) to high temperatures (50 to 60 • C) indicated that the absorbing species and/or the injury and response mechanisms may be different from injuries caused by prolonged exposure to moderately elevated temperatures (40 to 50 • C for 10 to 20 min).…”