AbstractNon-freezing cold injury (NFCI) is caused by protracted skin cooling above the freezing point of tissue and up to ~15 °C which predominantly afflicts the extremity skin sites owing to their enhanced vasoconstrictor response to cooling. This cold injury may cause long term symptoms, possibly debilitating an individual for their lifetime. Whilst pain and excessive sweating of the injured skin site are common features, some individuals may appear asymptomatic until they are exposed to cold where they may experience an augmented vasoconstrictor response and rewarm slower than those without NFCI, thereby exposing those individuals to further cold injuries.
Compared with Caucasians (CAU), individuals of African descent (AFD) are more susceptible to NFCI. The reason for the increased susceptibility in AFD is not known but may be due to a lower skin blood flow (SkBF) and therefore skin temperature (Tsk) during cooling and subsequent rewarming. There are no data investigating extremity (i.e. hand and foot) cooling and subsequent rewarming responses between ethnic groups. Additionally, it is not known how individuals of Asian descent (ASN) compare with these two ethnicities. Therefore, a series of studies are reported in this thesis that studied the ethnic difference in the response to cold and provided data on the mechanisms responsible for the differences observed between ethnic groups.
The approach of the experiments described in this thesis followed in vivo testing of young healthy male participants from different ethnic groups. Study One demonstrated that local hand cooling (30 minutes at 8 °C) caused more intense and protracted finger vasoconstriction in AFD than CAU. Additionally, AFD experienced an onset of finger vasoconstriction sooner than CAU during progressive cooling. ASN responses were between that of AFD and CAU. The Tsk responses to local foot cooling (two minutes at 15 °C) were not different between ethnic groups. As ASN did not demonstrate measureable differences compared with the other ethnic groups they were not examined in the subsequent studies. In Study Two the responses to transdermally delivered vasoactive agents were studied in the extremities. The vasodilator response to the endothelium-dependent vasodilator, acetylcholine (ACh), was smaller in AFD than CAU in the non-glabrous finger and toe skin sites. These skin sites did not demonstrate any differences between ethnicities in response to an endothelium-independent vasodilator, sodium nitroprusside, or the vasoconstrictor noradrenaline. These studies provided evidence in support of an altered endothelium function in AFD which may contribute to the exaggerated vasoconstrictor response and slower rewarming in this group.
In Study Three the responses to ACh were studied in the presence of cyclooxygenase (COX) inhibition, as this enzyme may be stimulating reactive oxygen species (as well as prostanoids) causing endothelium-dependent contracting factors. The results indicate that the vasodilator responses to local application of ACh in the non-glabrous foot and finger skin sites were lower in AFD than CAU irrespective of whether COX was inhibited or not. This study suggests that the COX pathway is not the primary source of dysfunction causing the lower vasodilator responses in AFD compared with CAU. However, the contribution of the COX pathway during local foot and hand cooling and rewarming in CAU and AFD is not known, therefore, Study Four investigated the vascular responses with and without COX inhibition. Following placebo, SkBF and Tsk did not differ between ethnic groups at the toe pad skin site during foot cooling (30 minutes at 8 °C). Following aspirin consumption the toe pad skin site was cooler in CAU than AFD but SkBF did not differ between groups. During hand cooling (30 minutes at 8 °C) AFD experienced significantly lower finger SkBF and Tsk compared with CAU irrespective of whether COX was inhibited or not.
The studies in this thesis collectively demonstrate: 1) AFD respond to local hand cooling with an earlier onset of vasoconstriction, greater skin cooling and slower rewarming, and 2) the microcirculation of the non-glabrous skin sites of the foot and finger in AFD appears to exhibit a reduced response to ACh. The increased prevalence of NFCI in AFD may be attributable to the greater and sustained vasoconstrictor response to local cooling in the hands. The mechanisms controlling this response in AFD are not clear, but do not appear to be directly attributable to the COX pathway. The local foot cooling responses, which were largely comparable between AFD and CAU, highlights that there are other differences between ethnic groups which lead to the increased prevalence of NFCI in AFD.
|Date of Award
|Clare Eglin (Supervisor), James R. House (Supervisor) & Mike Tipton (Supervisor)