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INVITED EDITORIAL
Department of Applied Physiology, and Center for Exercise Science, University of Florida, Gainesville, Florida
VISIONS OF SPACE TRAVEL have long captured the human imagination, as illustrated by the literary works of Jules Verne's From the Earth to the Moon, H. G. Wells' The First Men in the Moon, and Edgar Rice Burroughs' A Princess of Mars, and through the adventures of the comic strip heroes Buck Rogers and Flash Gordon. However, such desire and yearning for space travel clashed with concerns of possible catastrophic consequences to the human body on entering a microgravity environment. Early test flights with animals demonstrated that such ventures in space were technically dangerous but medically feasible. From there, the early experiences of the Soviet Vostok and Voskhod missions and the US Mercury, Gemini, and Apollo programs in the 1960s indicated that humans could function quite well in a weightless environment. But even in these early programs, there were clear indications that microgravity could have adverse consequences on the body, particularly when transitioning from Earth to space and back. Today with space travel and exploration becoming an increasingly international enterprise and with nearly 50 years of manned spaceflight experience, we have discovered a great deal about the biomedical consequences of habitation in a microgravity environment, but much is yet to be learned.
One such area of biomedical research where little is known is the effects of mechanical unloading and physical deconditioning on wound healing. Several studies have indicated that spaceflight can adversely affect tissue repair in muscle and bone (1, 6, 7, 10). For example, Davidson et al. (2) conducted a study to determine the effects of microgravity on intrinsic wound healing in rats. These investigators subcutaneously implanted sponges with a pellet to release either a placebo or one of several growth factors to investigate the capacity of spaceflight and ground-based animals to form granulation tissue and collagen, important components in wound healing. The results indicated that microgravity adversely affects the capacity of wounds to heal and that this may be related to a diminished cellular response to growth factors known to be present at sites of wounding (2). Although other anecdotal evidence exists to support this conclusion, there are few other direct data addressing the problem of wound healing in a low gravitational stress environment.
One of the primary obstacles for investigating microgravity-associated impairment of wound healing, tissue repair, or any other bodily dysfunction is the paucity of research opportunities in space. Furthermore, mechanical unloading and physical deconditioning, which are thought to be central components in the effects of microgravity on the human body, have much broader clinical applications on Earth, for example as it relates to prolonged bed rest or inactive geriatric patients. As a result, ground-based animal models have been used to mimic the mechanical unloading and physical deconditioning associated with microgravity and bed rest in humans. One such model is the tail-suspended hindlimb-unloaded rat (13). Using this model, Martinez et al. (8) investigated ligament healing and found that unloading impaired dense fibrous connective tissue wound healing. Thus these results of ligament healing in hindlimb-unloaded rat were consistent with the findings of attenuated muscle and bone healing in rats flown in space (1, 6, 7, 10).
The collective literature regarding wound healing with mechanical unloading and physical deconditioning largely points to deficits in the inflammatory phase, characterized by immune cell infiltration (2), and the remodeling phase, which includes collagen accumulation and cross-linking (2, 8, 10). However, large gaps in our understanding of the wound healing process remain, including events associated with the proliferative phase (e.g., angiogenesis) and whether mechanical unloading before wound induction affects the healing process. Therefore, the study of Radek et al. (11) in the Journal of Applied Physiology is significant because it addresses several aspects of impaired wound healing associated with unloading and deconditioning that have not been previously investigated.
Using the hindlimb-unloaded rat, Radek et al. (11) tested the hypothesis that 2 wk of prior unloading and deconditioning would delay wound healing in cutaneous tissue. Wounds were analyzed for wound closure, angiogenesis, and collagen content from 3 to 21 days postwounding. Unlike previous work (2, 8, 10), the results suggested that collagen formation was not affected by unloading, as indicated by the lack of difference in hydroxyproline concentration, an index of total collagen content, between control and unloaded groups at any time postwounding (11). However, the results demonstrated that epithelial cell migration across the wound bed and wound closure were delayed in the hindlimb-unloaded rats. In addition, wounds from unloaded animals demonstrated a lower vascular density during the initial postwounding period, and the vasculature that was present in these rats lacked much of the directional growth toward the epithelium that was apparent in control animals. These results collectively indicate that both keratinocyte and endothelial cell function are impaired during wound healing with mechanical unloading and deconditioning.
Several possible mechanisms were proposed to explain these observations. The diminished rate of dermal keratinocyte wound migration could result from excess inflammation in the unloaded rats, since inflammation may inhibit keratinocyte migration (4), and neutrophil infiltration into the epidermis and dermis was found to be greater in the unloaded rat wounds (11). Tissue blood flow also plays an important role in the movement of neutrophils from the vascular space to the site of the wound. Although the effects of unloading and deconditioning on blood flow to a wounded area have not been reported, hindlimb unloading is known to alter tissue perfusion patterns in rats (9).
Another important function of keratinocytes in tissue repair is the secretion of various factors that can attract endothelial cells for revascularization of the wound area. One key mediator of endothelial cell migration and angiogenesis is vascular endothelial growth factor (VEGF). Although measured VEGF concentrations were not statistically different between unloaded and control rats, the statistical tendency for a decrease and the absolute reduction of 
25% in VEGF concentration during the initial phase of the wound healing suggests that VEGF may be a biologically important factor, among others, in the delay and apparent disorganization of revascularization in the wound area of hindlimb-unloaded rats (11). Previous studies have also demonstrated vascular endothelial cell dysfunction in hindlimb-unloaded rats (3, 12), but this dysfunction has been associated with the role that the endothelium plays in regulating vascular tone and tissue perfusion. Hindlimb unloading has also been reported to impair the function of the lymphatic circulation in rats (5), which could diminish infiltration of lymphocytes into the wound area during the inflammatory phase of healing, as well as attenuate growth factor signaling for angiogenesis in the proliferative phase of healing. Thus the effects of altered hemodynamics (9) and other factors associated with mechanical unloading and deconditioning on the lymphatic circulation, lymphocyte and plasma cell migration and function, growth factor signaling, and the multiple roles played by endothelial cells in tissue perfusion regulation and angiogenesis remain fertile areas of future investigation to determine their impact on wound healing. The work of Radek and colleagues (11) has done much to elucidate the effects of mechanical unloading and deconditioning on the complex events that take place during the various phases of wound healing, but like many seminal studies in science, it has opened more areas of inquiry than it has answered.
FOOTNOTES
Address for reprint requests and other correspondence: M. D. Delp, Dept. of Applied Physiology, and Center for Exercise Science, Univ. of Florida, Gainesville, FL 32611 (e-mail: mdelp{at}ufl.edu)
REFERENCES
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