Archives of Dermatological Research

, Volume 304, Issue 6, pp 451–457 | Cite as

Role of cellular oxidative stress and cytochrome c in the pathogenesis of psoriasis

Original Paper

Abstract

Oxidative-free radicals and apoptosis have linked to chronic skin diseases. Higher levels of oxidative radicals and the release of mitochondrial cytochrome c may have a role in the pathogenesis of psoriasis. We investigated the possible role of cellular oxidative stress and release of cytochrome c of mitochondria in the pathogenesis of psoriasis. Disease severity was assessed by psoriasis area severity index score (PASI) of 55 psoriasis patients, they grouped as mild (11), moderate (20) and severe (24), also 20 healthy individuals used as controls. All groups were subjected for serum malondialdehyde (MDA), nitric oxide (NO·), superoxide dismutase (SOD), catalase (CAT), total antioxidant status (TAS) and serum cytochrome c concentrations. We found that, (1) Severity wise increase in MDA and NO·, and decrease in SOD, CAT and TAS levels in all patients with different degrees of psoriasis; (2) PASI showed positive correlation with the increase in MDA and NO·, and negatively with decreased SOD, CAT and TAS levels; (3) significant increase in cytochrome c level was observed among psoriasis patients which showed negative correlation to MDA and NO· levels in mild and positively with moderate and severe groups. The release of mitochondrial cytochrome c indicates the induction of apoptosis mediated via oxidative stress which ultimately plays role in the pathogenesis of psoriasis.

Keywords

Mitochondria Psoriasis PASI score Apoptosis cytochrome c Oxidative stress Antioxidant status Antioxidant enzymes 

Introduction

Chronic psoriasis is an immune-mediated inflammatory skin condition occurs before the age of 35 and affecting approximately 2 % of the general population. Psoriasis considered as a lifelong disease with a heavy burden on quality of patient’s life [24]. The exact pathogenesis of this disease is still unknown. Recent studies showed that, the skin is a potential target for oxidative injury caused via reactive oxygen species (ROS) as nitric oxide (NO·), hydrogen peroxide (H2O2) and malondialdehyde (MDA) which may damage cell compounds such as protein, lipid and DNA [1, 35, 46]. A complex of human antioxidant enzymes catalyzes the reaction of ROS scavenging. Those are superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) [51]. Over production of ROS especially MDA in chronic inflammatory processes have been shown to participate in tissue lesion. Also, the decreased activity of antioxidants may play a role in the pathogenesis of psoriasis [1, 11, 18]. Other studies investigated the role of NO· , H2O2 and MDA in psoriasis. These deadly hydroxyl radicals damage cellular constituents and increase the severity of psoriasis [6, 12, 49].

The increased epidermal thickness and altered tissue architecture observed in psoriasis may be related to an abnormality in the apoptotic pathways and oxidative stress of non-differentiated keratinocytes which triggers the formation of defective horny layer, the key mechanism of psoriasis [2, 23, 39]. In certain cell types, the apoptosis requires the death of mitochondria to amplify the apoptotic response which signed with cytochrome c release from the mitochondria [8, 15]. In psoriasis, keratinocyte apoptosis via mitochondria was reported. The disruption of mitochondrial membrane and endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis [30]. Until recently it was difficult to treat psoriasis due to incomplete understanding of the factors behind pathogenesis of psoriasis. Therefore, the aim of this study was to determine the oxidative stress, the release of mitochondrial cytochrome c and its correlation with the severity of the psoriasis.

Patients and methods

Patients

A total of 75 individuals selected from patients admitted to dermatology department, faculty of medicine, Mansoura University, Mansoura, Egypt. Out of these 20, age and sex-matched healthy individuals (12 men and 8 women, between 14 and 66 years of age) with a mean age of 23 ± 1.5 were selected as controls. Fifty-five psoriatic patients (35 men and 20 women, aged from 11 to 64 years of age) with a mean age of 29 ± 13.6 were included in this study. Patients and control subjects who were alcoholics or smokers and had past or concurrent diseases like anemia, abnormal lipid profile, diabetes mellitus, cardiovascular diseases, liver or kidney diseases and inflammatory skin diseases which may possibly affect the redox status were excluded from the study. Also subjects with overweight and obesity (BMI ≥25 and ≥30 kg/m2) were excluded from the study. Psoriatic patients with any topical therapy within 4 weeks, systemic drug therapy or photo chemotherapy within 3 months were excluded from this study. The demographics and baseline characteristics of psoriatic patients and controls are presented in Table 1. The study protocol was approved by ethical committee of the dermatology department.
Table 1

Demographics and baseline characteristics of psoriatic patients and healthy control groups (mean ± SD)

Parameters

Study group (n = 55)

Control group (n = 20)

P value

Age (years)

29 ± 13.6

23 ± 1.5

0.1

BMI (kg/m2)

23.6 ± 4.4

22.12 ± 4.4

0.3

Duration of psoriasis (years)

4.72 ± 1.7

PASI score classification

 Mild (PASI up to 25)

21.82 ± 1.164 (n = 11)

 Moderate (PASI ≥25)

49.85 ± 2.62 (n = 20)

 Severe (PASI ≥50)

62.9 ± 11.13 (n = 24)

Psoriasis area and severity index (PASI)

The patients were diagnosed by Auspitz sign, clinical features of psoriasis like erythema, itching, thickening and scaling of skin. Disease duration of the patients ranged from 5 months to 10 years with mean range (5.4 ± 4). The clinical severity was determined according to the psoriasis area and severity index (PASI) [28]. PASI assesses four body regions, the head, trunk, upper extremities and lower extremities. For each region, the surface area involved is graded from 0 to 6 and each of three parameters (erythema, thickness and scaling of the plaques) is graded from 0 to 4. The scores from the regions were summed to give a PASI score ranging from 0 to 72. Psoriatic patients were classified into mild (11 patients; PASI up to 25), moderate (20 patients; PASI ≥25) and severe (24 patients; PASI ≥50). Peripheral venous blood samples were obtained from patients and controls in the morning following an overnight fast. Then, serum samples were aliquoted in smaller containers and stored at −80 °C until assaying.

Blood analysis

Measurement of oxidative free radicals

Malonaldehyde MDA was determined by the thiobarbituric acid method according to Satoh [38], and the absorbance of thiobarbituric acid reactive substances (TBARS) was measured at 532 nm. The data of TBARS were expressed in MDA, using a molar extinction coefficient for MDA of 1.56 × 105/cm/m and the results were expressed in nmol/ml.

Serum nitric oxide NO· levels were measured with Griess reagent as described previously [7, 31]. The first step is conversion of nitrate using nitrate reductase. The second step is addition of Griess reagent, which converts nitrite to a purple azo-compound. Protein interference was avoided by treatment of the reacted samples with zinc sulphate and centrifugation for 5 min at 10,000g; the formed azo-compound was measured at 450 nm; sodium nitrate was used as the standard and results were expressed in mmol/l.

Measurement of serum antioxidant enzymes

All patients and control subjects were examined for SOD and CAT activities. SOD and CAT activities were measured as described previously [14, 42]. One unit of SOD activity was defined as the enzyme protein amount causing 50 % inhibition in nitro blue tetrazolium (NBT) reduction rate and the results were expressed as U/ml.

Measurement of total antioxidant status (TAS)

The method for serum TAS determination was as previously described by Kampa [19]. In brief, in each tube 400 μl of crocin and 200 μl of serum sample were pipetted. The reaction was initiated with the addition of 400 μl of pre-warmed (37 °C) ABAP (5 mg/ml) and crocin bleaching was made by incubating the plate in an oven for 60–75 min. Blanks consisting of crocin, serum samples and phosphate buffer (400, 200 and 400 μl, respectively) were run in parallel. The absorbance was measured at 450 nm. A standard curve of the water soluble synthetic antioxidant Trolox, prepared prior to use, ranging from 0 to 10 μg/ml was equally assayed under the same conditions.

Determination of apoptotic marker by ELISA

Serum cytochrome c concentrations were determined using an enzyme-linked immunosorbent sandwich assay kit (Zymed®cytochrome c ELISA Kit Cat. No. 99-0040).

Statistical analysis

Variables were summarized by standard descriptive statistics and expressed as mean ± SD. The results obtained were analyzed statistically using the unpaired Student’s ‘z’ test, to evaluate the significance of differences between the mean values. Spearman’s correlation was used to calculate the association of variables between groups. P values >0.05 were considered statistically significant. All statistical analysis were performed using the SPSS 11.5 package program.

Results and discussion

Psoriasis is a common and chronic skin disorder, the pathogenesis of which is incompletely understood. Results from various clinical and experimental studies indicate that psoriasis is a complex multifactorial disease with a genetic predisposition. Oxidative stress (OS) and increased free-radical generation have been linked to skin inflammation in psoriasis [34].

Increased production of free radicals or ROS may cause oxidative damage on biological molecules, cell membranes and tissues. It induced oxidation of polyunsaturated fatty acids in biological system, results in the formation of lipid peroxidation products such as MDA which is used as a biomarker of lipid peroxidation [1, 29]. Higher plasma lipoperoxidation products and a correlation with disease severity have been reported in patients with psoriasis previously [37, 52]. However, Yildirim et al. [51] did not detect any difference in serum MDA levels in psoriatic patients compared to controls.

The present study shows that serum MDA levels were significantly increased in mild (P < 0.001), moderate (P < 0.001) and severe (P < 0.001) psoriatic patients as compared with healthy controls. Furthermore, we found severity wise increase in MDA levels in these patients indicating that the degree of elevation of serum MDA is associated with the progression of psoriasis (Table 1). This matched with Vanizer et al. [48] who reported a high plasma MDA levels and lower antioxidant defense enzymes in the keratinocytes of patients with severe psoriasis. ROS may be produced during the inflammatory process in psoriasis affecting primarily lipid metabolism of cells. Further ROS that are produced by lipid peroxidation may activate phospholipase A2 and thus cause peroxidation of many mediators by arachidonic acid which finally metabolized to MDA [51].

In the patient group, the mean diseases duration was 4.72 ± 1.7 (range 5 months to 10 years). In severe psoriatic patients, there was statistically significant (P < 0.001) correlation between the disease duration and the severity of psoriasis compared to mild and moderate groups (Table 2). We also found a positive significant (P < 0.001) correlation between disease duration and both MDA and NO· along with negative significant (P < 0.001) correlation with SOD, CAT and TAS in severe psoriatic patients compared to mild and moderate groups (Table 2). The disease duration may play a significant role in the severity of disease increasing both abnormal immune reactions and oxidative free radicals (Table 3).
Table 2

Oxidative stress and severity of psoriasis (PASI) measuring by the values of MDA, NO·, TAS, SOD, CAT, cytochrome c in control and psoriasis patients

Parameters

Units

Controls (group I)

Mild psoriasis (group II)

Moderate psoriasis (group III)

Severe psoriasis (group IV)

Number of subjects

20

11

20

24

PASI score

21.82 ± 1.164

49.85 ± 2.62

62.9 ± 11.13

Serum MDA

μmol/l

1.32 ± 0.5

3.59 ± 0.47*

4.24 ± 0.57*,#

5.1 ± 0.53*,#,§

Serum NO·

μmol/l

8.24 ± 1.71

12.65 ± 1.7*

17.5 ± 3.7*,#

20.45 ± 2.87*,#,§

Serum SOD

U/l

41.97 ± 7.8

16.84 ± 3.24*

11.33 ± 4.3*,#

9.52 ± 2.68*,#,§

Serum CAT

kU/l

69.54 ± 8.55

45.913 ± 9.5*

24.92 ± 6.73*,#

21.36 ± 5.9*,#,§

Serum TAS

μmol/l

972.6 ± 44.45

865.3 ± 27.82*

822.2 ± 33.45*,#

709.0 ± 27.37*,#,§

Serum cytochrome c

ng/ml

24.20 ± 8.9

236.0 ± 11.05*

252.24 ± 13.9*,#

269.34 ± 12.24*,#,§

Duration of psoriasis

years

2 ± 0.4*

3.63 ± 1.0*,#

4.84 ± 2.18*,#,§

Values are expressed as mean ± SD

P < 0.001 as compared to group I, # P < 0.001 as compared to group II, § P < 0.001 as compared to group III

Table 3

Correlation analysis of different parameters among groups of psoriasis patients

Parameters

Psoriatic patients (n = 55), R

Mild (n = 11)

Moderate (n = 20)

Severe (n = 24)

MDA/NO·

+0.077*

+0.32*,#

+0.311*,#,§

MDA/SOD

−0.076*

−0.352*,#

−0.135*,#,§

MDA/CAT

−0.099*

−0.034*,#

−0.24*,#,§

MDA/TAS

−0.091*

−0.298*,#

−0.173*,#,§

MDA/cytochrome c

−0.041*

+0.30*,#

+0.027*,#,§

NO·/TAS

−0.32*

−0.23*,#

−0.04*,#,§

NO·/cytochrome c

−0.372*

+0.124*,#

+0.093*,#,§

MDA/duration of psoriasis

0.49*

0.36*,#

0.11*,#,§

NO·/duration of psoriasis

0.03*

0.07*,#

0.07*,#,§

TAS/duration of psoriasis

−0.29*

−0.032*,#

−0.16*,#,§

SOD/duration of psoriasis

−0.21*

−0.018*,#

−0.04*,#,§

CAT/duration of psoriasis

−0.38*

−0.26*,#

−0.42*,#,§

R values are significant (P < 0.05)

P < 0.001 as compared to group I, # P < 0.001 as compared to group II, § P < 0.001 as compared to group III

Fibroblasts in the lesion-free skin of psoriatic patients show signs of increased oxidative damage, even before the formation of characteristic psoriatic lesions which may be involved in the abnormal immune reactions, leading to the onset of the disease [10]. As a potential regulator of keratinocyte growth and differentiation, the multifunctional signaling molecule NO· has been considered to be a strong candidate marker of inflammation in the pathogenesis of psoriasis [5, 45].

In the present study, there was statistically significant increase in the levels of NO· end products in mild (P < 0.001), moderate (P < 0.001) and severe (P < 0.001) psoriatic patients when compared with healthy controls. Furthermore, NO· end product levels in moderate psoriatic patients were significantly higher (P < 0.001) than in the patients presenting with mild psoriasis, whereas severe psoriatic patients exhibited a significant rise in serum NO· end products (P < 0.001) as compared to moderate psoriasis (Table 2). We also found a positive correlation between MDA and NO· end products among the three different groups of psoriatic patients. This finding shows extensive cohesiveness that generates NO· end products in excess may also trigger lipid peroxidation process (Table 3).

Increased expression of iNOS mRNA in skin lesions is involved in the pathogenesis of cutaneous inflammation in psoriasis [33, 41].

Also, Orem et al. [32] observed that nitrite levels and nitrite–nitrate ratios appear to be good indicators for the increased NO· production in patients and also showed a significant correlation with PASI score.

In vivo antioxidant status can be assessed by measuring individual plasma or tissue levels of antioxidants. Measuring the levels of TAS provides an overall indication of antioxidant status. So, the researchers are recently focused on oxidative stress as one of the important factor in pathogenesis of psoriasis [1, 35, 37].

In this study, we found that the serum TAS levels were significantly decreased in mild (P < 0.001), moderate (P < 0.001) and severe (P < 0.001) psoriatic patients as compared with healthy controls. Furthermore, the TAS levels in moderate psoriatic patients were significantly lower (P < 0.001) than in the patients presenting with mild psoriasis; whereas, severe psoriatic patients exhibited a significant decrease in plasma TAS levels (P < 0.001) as compared to moderate psoriasis (Table 2). We further found a significant negative correlation between plasma TAS and serum MDA levels among the three different groups of psoriasis. This correlation signifies that decreased TAS may increase lipid peroxidation, which may be a consequence of sustained decreased TAS (Table 3).

We also found significant negative correlation between plasma TAS and serum NO· end product levels among the three different groups of psoriasis. Since all NOS isoforms generate O2·− which was markedly increased in skin lesions and the keratinocytes. This is the reason why we found the negative correlation between NO· end product and TAS among different groups of psoriasis [21].

The decreased TAS may be possibly due to the depressed state of antioxidant system or due to the exaggerated inflammatory processes and oxidative stress in psoriasis patients [20]. Antioxidants prevent oxidative injury of structural lipids and proteins contributing to barrier integrity which is essential for healthy skin condition. This suggests that cellular redox environment plays a pivotal role in skin homeostasis and that skin disease could result from an imbalance between pro-oxidant and antioxidant stimuli [3].

SOD, an antioxidant enzyme accelerates the dismutation of the toxic superoxide radicals produced during the oxidative energy processes into the less harmful molecules, hydrogen peroxide and molecular oxygen [40]. It has been suggested that increased generation of superoxide anion radicals from neutrophils and neutrophil accumulation in psoriatic lesions may cause abundant superoxide production during the phagocytic reaction and systemic activation of circulating neutrophils in psoriatic patients [47].

In the present study, we observed that serum SOD activities were significantly decreased in mild (P < 0.001), moderate (P < 0.001) and severe (P < 0.001) psoriatic patients as compared with healthy controls. Furthermore, SOD activity in moderate psoriatic patients was significantly lower (P < 0.001) than in the patients presenting with mild psoriasis; whereas, severe psoriatic patients exhibited a significant decrease in SOD activity (P < 0.001) as compared to moderate psoriatic patients (Table 2). We also found a negative correlation between SOD activity and serum MDA among the three different groups of psoriatic patients (Table 3).

Our study indicates the possibility that in the prediagnostic stage, serum antioxidants are low because they have been used in reducing inflammatory products. Decreased SOD activity might be related to epidermal hyper proliferation, because the ROS are thought to induce cell proliferation in various cell systems [26, 36].

We think that decreased SOD activity could be caused by increased superoxide anion production during the psoriatic process in the skin as well as activated peripheral neutrophils. Increased superoxide anion production could also induce lipid peroxidation as reflected by increased MDA levels. Increased oxygen metabolism has been described in the psoriatic hyper proliferative epidermis which depends on cutaneous blood flow. Increased O2·− production in the presence of decreased antioxidant activity would result in the accumulation of H2O2 which has an inhibitory effect on SOD activity [13]. Our findings are in consistent with the results of Kadam et al. [18] who reported a significant increase in level of MDA and decrease in the activity of GPx and SOD in patients with psoriasis.

In the process of removing superoxide free radicals, SOD rarely operates alone. It requires the enzyme called catalase. CAT and SOD always co-exist to remove hydrogen peroxide from our tissues preventing both cell damage and other more toxic free radicals.

The present study showed that there was statistically significant decrease in the activity of CAT in mild (P < 0.001), moderate (P < 0.001) and severe (P < 0.001) psoriatic patients when compared to healthy controls. Furthermore, serum CAT activity in moderate psoriatic patients were significantly lower (P < 0.001) than in the patients presenting with mild psoriasis; whereas, severe psoriatic patients exhibited a significant decrease in CAT activity (P < 0.001) as compared to moderate psoriatic patients (Table 2).We also found a negative correlation between CAT activity and serum MDA among the three different groups of psoriatic patients (Table 3). The CAT enzyme is most susceptible to the effect of UV radiation in the epidermis. Its activity can be affected by high peroxide concentration and by visible light [10]. Keratinocytes generate the O2·− is known to inhibit CAT. Furthermore inactivation of SOD would lead to build-up of H2O2 which have also been reported to induce CAT inactivation [13].This might be the reason behind a negative correlation between MDA and CAT.

Apoptosis is involved in development elimination of damaged cells and maintenance of cell homeostasis. However, deregulation of apoptosis may cause diseases such as cancer immune diseases and psoriasis [9]. Under certain pathological conditions, the cellular ROS level increases significantly which may cause the oxidative damage of various cellular components and finally cell death [17]. In mammalian cells, ROS production causes cytochrome c release from mitochondria which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death [22, 27]. Also, it was reported that mitochondria are strongly involved in production of reactive oxygen species considered as the main pathogenic agent of many diseases [25].

In this study, we found that the serum cytochrome c levels were significantly increased in mild (P < 0.001), moderate (P < 0.001) and severe (P < 0.001) psoriatic patients as compared with healthy controls. Furthermore, the cytochrome c levels in moderate psoriatic patients were significantly higher (P < 0.001) than in the patients presenting with mild psoriasis; whereas, severe psoriatic patients exhibited a significant higher (P < 0.001) in serum cytochrome c levels as compared to moderate psoriasis (Table 2). This matched with other studies which reported that during apoptosis cytochrome c is released from mitochondria to activate a caspase cascade which commits the cell to the death process [4, 43, 50].

We also found that the increase of cytochrome c level correlates (P < 0.001) negatively with MDA and NO· in mild and positively (P < 0.001) in moderate and severe psoriasis patients (Table 3). This finding shows that the induction of apoptosis mediated via oxidative stress plays role in the pathogenesis of psoriasis. Our finding supports other studies showing oxidative stress and its involvement in the pathogenesis of psoriasis through mitochondrial oxidative damage [16, 44].

Conclusion

In conclusion, this study finding suggests that increased reactive oxygen species along with insufficient total antioxidant capacity as well as apoptosis via mitochondria may be involved in the pathogenesis of psoriasis.

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Anatomy, Faculty of MedicineMansoura UniversityMansouraEgypt
  2. 2.Rehabilitation Research Chair (RRC)King Saud UniversityRiyadhSaudi Arabia
  3. 3.Department of Rehabilitation Science, College of Applied Medical SciencesKing Saud UniversityRiyadhSaudi Arabia

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