A System Out of Breath: How Hypoxia Possibly Contributes to the Pathogenesis of Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular alterations and immunological disturbances and fibrosis, the order of which remains to be fully determined. Clinically, patients show clear signs of hypoxia in skin and internal organs. The low oxygen tension is potentially caused by a yet to be indentified circuitry involving the three features that typify SSc. In addition, once present, the hypoxia creates a vicious circle of ongoing pathology. In this paper, we provide an overview of the evidence that points towards the mechanisms causing hypoxia in SSc. In addition, data that suggest how hypoxia itself may orchestrate worsening of symptoms is presented. Altogether, it is clear that hypoxia is an important hallmark in SSc patients. By providing an overview of the mechanisms at play and the possible therapeutic avenues that have emerged, we hope to stimulate researchers to provide novel clues into the conundrum in SSc patients.

Expression of the oxygen-sensitive transcription factor subunit HIF-1α in patients suffering from secondary Raynaud syndrome

“…In patients suffering from autoimmune diseases, such as the connective tissue disease systemic sclerosis (SS), the extent of oxidative stress and hypoxia is associated with patient outcome and therapeutic success [9]. Consequently, HIF-1 has become of great interest in the current research in this field, particularly since it has been shown to be involved in persistent pathofibrogenesis and vascular remodeling in SS [10][11][12].…”

Hypoxia induced interstitial transformation of microvascular endothelial cells by mediating HIF-1α/VEGF signaling in systemic scleroderma

“…Previous studies have con rmed that hypoxia could induce EndMT in various diseases, including scleroderma, which contributes to the vicious circle of ongoing pathology, and is considered as an important hallmark in SSc patients [6][7][8][28][29][30]. The Galectin-3, Endothelin-1 (ET-1), HIF-1α/Twist1, BMP-7/Smads and TGFβ1/SMAD signaling pathways have been proven to be critical mediators in PAH by regulating EndMT, and have a critical role in mediating the effect of hypoxia-induced EndMT in pulmonary arterial and cardiovascular remodeling [6,8,29,30].…”

Skin oxygen tension is improved by immersion in oxygen‐enriched water

“…A detailed vascular and neurologic assessment of the lower limb was performed to establish the physiologic health of skin being treated with O 2 -H 2 O. Macrovascular, microvascular and neuro-pathic disease can reduce nutritive blood flow in the skin [4,5] causing lower than normal PskO 2 values. In general, increasing age was associated with some decline in the resistive element (P.I.)…”

“…Epidermal O 2 to support metabolic function is supplied by O 2 diffusion from the underlying dermal capillary bed or by way of direct O 2 absorption across the stratum corneum from air in contact with the skin surface [1,2]. Cutaneous hypoxia is associated with poor regenerative capacity and can result from altered dermal blood flow due to scleroderma-and diabetic-based microvascular pathology [4,5]. Cutaneous hypoxia is associated with poor regenerative capacity and can result from altered dermal blood flow due to scleroderma-and diabetic-based microvascular pathology [4,5].…”

“…Elevated skin oxygen levels are associated with a subjective appearance of good health and beauty [3]. Cutaneous hypoxia is associated with poor regenerative capacity and can result from altered dermal blood flow due to scleroderma-and diabetic-based microvascular pathology [4,5]. O 2 diffusion in the epidermis follows Fick's first law where the diffusion rate and diffusion distance are proportional to the pressure gradient given the surface area (SA) and solubility of the diffusing substance (K D ).…”