Cold and Stress Trigger Adrenaline, Aggravate Skin Fibrosis, Study Says

Exposure to low temperatures and emotional stress triggers the production of norepinephrine (adrenaline), which contributes to skin fibrosis in patients with systemic sclerosis (SSc), a new study says.

The study, “Mechanistic Insight Into The Norepinephrine-Induced Fibrosis In Systemic Sclerosis”, published in the journal Scientific Reports, was conducted by a group of Japanese researchers.

Systemic sclerosis is characterized by the development of fibrosis in the skin and other organs, and dysfunction of blood vessels. Several SSc patients also have Raynaud’s phenomenon, a disease in which cold temperatures or emotional stress cause the narrowing of blood vessels in the hands and feet for a period of time, decreasing blood flow in those regions and leading to cell death.

It is well-known that cold and emotional stress also induce the systemic or local increase in adrenaline levels. In fact, SSc patients treated with antagonists of the adrenaline receptor showed improvement in symptoms of Raynaud’s phenomenon induced by low temperatures, which suggests that adrenaline may play an important role in the blood vessel abnormalities of SSc. However, the exact role of adrenaline in the development of skin fibrosis in SSc is not well-known.

To address this question, cell cultures derived from skin biopsies of six SSc patients and six healthy matching control subjects were stimulated with adrenaline. Researchers then analyzed the levels of interleukin (IL)-6, an immune protein whose production can be induced by adrenaline and that has been shown to be associated with skin lesions in SSc.

The results indicated that adrenaline induces IL-6 production in skin cells from both normal and SSc subjects in a dose- and time-dependent manner, but IL-6 production is significantly higher in cells from SSc patients.

Researchers also observed that the molecular pathway leading to the onset of skin lesions and fibrosis initiates with activation of the adrenaline receptor (ARβ), and includes the activation of several proteins, such as proteins p38 and STAT3, ultimately culminating in IL-6 production. By using specific drugs that inhibit each of these proteins, the team was able to block the effect triggered by adrenaline stimulation and consequently reduce the development of skin fibrosis.

“Since the peripheral tissues of the extremities, including the fingers and toes, are likely to be exposed to cold stimulation, cold stimulation-induced [adrenaline] may increase the IL-6 concentrations locally, resulting in peripheral skin sclerosis in SSc patients,” the authors wrote. “This may also explain why the onset of skin fibrosis initially starts from the acral parts of the extremities. Furthermore, our results suggest that avoiding cold exposure or emotional stress may suppress both fibrosis and Raynaud’s phenomenon in SSc.”

The study’s authors also suggested that drugs affecting the molecular pathway responsible for the skin lesions can be an alternative treatment for skin sclerosis in patients with SSc.