lipopolysaccharide endotoxins in circulation, potentially triggering a generalized inflammatory response through TLR-4 and CD14.66 Overall, research to date supports a link between microbiome alterations, systemic inflammation, and overall health. We are in the early stages of understanding and defining details related to the microbiome, both overall and within specific body systems such as skin. Thus far, there is good evidence to show that the status of the microbiome plays an important role in maintaining overall health homeostasis and can contribute to the pathophysiology of specific disease states including AV.
Hormones
The role of the endocrine system, especially androgens, is well-established as a mandatory component in the development of AV.67 In the 1930s, the correlation between a woman's menstrual period and AV led doctors to label AV as "chastity pustules," for which they prescribed laxatives to help rid the body of the build-up of toxins.68 Over almost a century, our understanding of the skin and AV has come a long way, and we now know that hormones, primarily androgens, drive AV in both men and women. It is also now recognized that the skin itself is an endocrine organ, capable of synthesizing androgens, such as dihydrotestosterone, within itself.67,69,70 A systematic review of over 1,000 studies found that testosterone and progesterone may be elevated in AV patients, but that estrogen is significantly lower in AV patients.71 Specifically, excess circulating androgens can be associated in some patients with AV, but many exhibit normal androgen levels on blood testing, supporting the important role of local androgen production in AV-affected skin.41,71 It has been shown that patients with AV produce higher levels of testosterone and 5alpha-dihydrotestosterone (DHT) in their skin than healthy individuals.41 It is also established that the sebocytes possess all the necessary enzymes for both synthesizing androgens and for converting testosterone to DHT, making the local skin environment the primary site for androgen activity in AV in most affected patients.71,72 DHT exerts its effects via the nuclear androgen receptor. It has been shown to directly stimulate TNF-alpha and IL-6, indicating a strong correlation between androgen activity in the skin and pro-inflammatory cytokine production in AV.73,74 The hormone DHEA also regulates sebum production and has been indicated as an important target in postmenopausal women.72 It also has been shown to be correlated with IGF-1 levels, which are higher in men and women with AV.72 As noted above, PCOS, an endocrine disorder induced by hyperandrogenism, is characterized clinically by the presence of AV as one of the visible manifestations of androgen excess.75
Oxidative Stress
The skin, and particularly the face, is regularly exposed to exogenous pollutants and irritants as well as UV radiation and ozone, leading to an accumulation of reactive oxygen species (ROS).76 These ROS, which are highly reactive and unstable chemical entities, have been shown to accelerate adverse skin changes including the appearance of aging and pigmentation, roughness, and wrinkles.76
On a mechanistic level, both intrinsic and extrinsic stressors can be a source of ROS generation: as a normal byproduct of mitochondrial metabolism; chronic psychological stress; environmental pro-oxidant factors including UVA, UVB, visible light, and infrared light exposure; and ozone exposure.76,80 ROS due to these stressors include superoxide radicals, hydrogen peroxide (H2O2), hydroxyls, singlet oxygens, peroxyl radicals, and nitric oxide (reactive nitric species).81 Our intrinsic antioxidant defense system is responsible for scavenging ROS and neutralizing them.81,82 This system includes enzymatic antioxidants, such as superoxide dismutase and catalase; non-enzymatic antioxidants such as glutathione, and vitamins C and E; and transcriptional activation of inflammatory responses in the follicular epithelium.80,83
Over time, and with overwhelming exposure to ROS sources, accumulation of ROS leads to oxidative damage to cellular components such as proteins, lipids, nucleic acids, and the cell membrane.80 Lipid peroxidation of the cell membrane, if subtoxic, may trigger repair mechanisms through antioxidant defense or signaling pathways that are adaptive.80 Otherwise, when the oxidative stress overwhelms the capacity of the cell to repair, it will trigger cellular damage, with functional impairment and sometimes necrosis, contributing directly to skin senescence.80 There are a few ROS-generating pathways specifically implicated in AV. Accumulation of neutrophils at the site of comedones leads to an increase in the generation of ROS.77 C. acnes has also been shown to induce neutrophil secretion of ROS.77
Lipid peroxidation, the oxidative degradation of lipids, is an important mechanism involved in the pathophysiology and progression of AV.80 Indeed, lipid peroxides, the chemical product, are higher in comedones of patients with AV and have been shown to affect keratinocyte proliferation and
Clinical evidence also indicates that oxidative stress may play a role in AV.77 Biomarkers for lipid peroxidation, such as blood serum levels of malondialdehyde (MDA), are significantly higher in patients with AV than in their controls.78 Enzymes with antioxidant capacity such as catalase, superoxide dismutase, and total antioxidant capacity are also significantly lower in patients with AV compared to controls, likely reflecting their consumption, at least partially, by interacting with ROS exposure with inadequate reserve.78 Accumulation of lipid peroxide (LPO) and sebum oxidation are also higher in comedones of patients with AV than from the facial stratum corneum.79 In addition to LPO, the inflammatory mediators IL-1alpha and NF-kappaB were also found to be higher in comedones, indicating a potential link between oxidative stress, inflammation, and AV lesion formation.79
On a mechanistic level, both intrinsic and extrinsic stressors can be a source of ROS generation: as a normal byproduct of mitochondrial metabolism; chronic psychological stress; environmental pro-oxidant factors including UVA, UVB, visible light, and infrared light exposure; and ozone exposure.76,80 ROS due to these stressors include superoxide radicals, hydrogen peroxide (H2O2), hydroxyls, singlet oxygens, peroxyl radicals, and nitric oxide (reactive nitric species).81 Our intrinsic antioxidant defense system is responsible for scavenging ROS and neutralizing them.81,82 This system includes enzymatic antioxidants, such as superoxide dismutase and catalase; non-enzymatic antioxidants such as glutathione, and vitamins C and E; and transcriptional activation of inflammatory responses in the follicular epithelium.80,83
Over time, and with overwhelming exposure to ROS sources, accumulation of ROS leads to oxidative damage to cellular components such as proteins, lipids, nucleic acids, and the cell membrane.80 Lipid peroxidation of the cell membrane, if subtoxic, may trigger repair mechanisms through antioxidant defense or signaling pathways that are adaptive.80 Otherwise, when the oxidative stress overwhelms the capacity of the cell to repair, it will trigger cellular damage, with functional impairment and sometimes necrosis, contributing directly to skin senescence.80 There are a few ROS-generating pathways specifically implicated in AV. Accumulation of neutrophils at the site of comedones leads to an increase in the generation of ROS.77 C. acnes has also been shown to induce neutrophil secretion of ROS.77
Lipid peroxidation, the oxidative degradation of lipids, is an important mechanism involved in the pathophysiology and progression of AV.80 Indeed, lipid peroxides, the chemical product, are higher in comedones of patients with AV and have been shown to affect keratinocyte proliferation and
