P-glycoprotein in autoimmune rheumatic diseases.

P-glycoprotein (Pgp) is a transmembrane protein of 170 kD encoded by the multidrug resistance 1 (MDR-1) gene, localized on chromosome 7. More than 50 polymorphisms of the MDR-1 gene have been described; a subset of these has been shown to play a pathophysiological role in the development of inflammatory bowel disease, femoral head osteonecrosis induced by steroids, lung cancer and renal epithelial tumors. Polymorphisms that have a protective effect on the development of conditions such as Parkinson disease have also been identified. P-glycoprotein belongs to the adenosine triphosphate binding cassette transporter superfamily and its structure comprises a chain of approximately 1280 aminoacid residues with an N-C terminal structure, arranged as 2 homologous halves, each of which has 6 transmembrane segments, with a total of 12 segments with 2 cytoplasmic nucleotide binding domains. Many cytokines like interleukin 2 and tumor necrosis factor alpha increase Pgp expression and activity. Pgp functions as an efflux pump for a variety of toxins in order to protect particular organs and tissues as the central nervous system. Pgp transports a variety of substrates including glucocorticoids while other drugs such as tacrolimus and cyclosporine A act as modulators of this protein. The most widely used method to measure Pgp activity is flow cytometry using naturally fluorescent substrates such as anthracyclines or rhodamine 123. The study of drug resistance and its association to Pgp began with the study of resistance to chemotherapy in the treatment of cancer and antiretroviral therapy for human immunodeficiency virus; however, the role of Pgp in the treatment of systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis has been a focus of study lately and has emerged as an important mechanism by which treatment failure occurs. The present review analyzes the role of Pgp in these autoimmune diseases.

Irritable bowel syndrome-type symptoms in female patients with mild systemic lupus erythematosus: frequency, related factors and quality of life.

BACKGROUND: Irritable bowel syndrome (IBS) impairs quality of life (HRQOL), as does systemic lupus erythematosus (SLE). Both are more common in women and are associated with fibromyalgia (FM). However, the relationship between IBS and SLE and its impact on HRQOL has not been explored. Therefore, we aimed to study the frequency and features likely to influence the presence of IBS-type symptoms in SLE and their impact on HRQOL. METHODS: Female patients with SLE were studied. The presence of IBS-type symptoms and bowel habit subtype were established by Rome III criteria and HRQOL was assessed using the SF-36. Fibromyalgia and depression were assessed using the American College of Rheumatology criteria and CES-D scale, respectively. KEY RESULTS: A total of 105 consecutive patients (43.62 ± 11.34 years old) were included; 48.6% had IBS-type symptoms (SLE+IBS) and were classified as IBS-C: 23.5%, IBS-D: 37.3%, and IBS-M: 39.2%. In addition, 23.8% had FM. SLE+IBS vs Non-IBS SLE patients had higher SLE activity scores (2.55 ± 1.65 vs 1.74 ± 2.19; p = 0.03), were more likely to have FM (33.0% vs 14.8%; p = 0.02) and depression (41.1% vs 25.9%, p = 0.04). Logistic multivariate analysis showed that IBS-type symptoms were associated with FM (OR = 2.85, 95% CI: 1.11-7.43) and depression (OR = 1.07, 95% CI: 1.02-1.13). Finally, SLE+IBS vs Non-IBS SLE patients had lower SF-36 scores (49.65 ± 18.57 vs 62.67 ± 18.14; p = 0.02). CONCLUSIONS & INFERENCES: IBS-type symptoms are highly prevalent among women with SLE and are associated with FM and depression. SLE+IBS patients had worse HRQOL vs Non-IBS SLE, independently of FM status. We suggest that treating IBS symptoms may improve HRQOL in women with SLE.

Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression.

During lung injury, fibroblasts migrate into the alveolar spaces where they can be exposed to pulmonary surfactant. We examined the effects of Survanta and surfactant protein A (SP-A) on fibroblast growth and apoptosis and on type I collagen, collagenase-1, and tissue inhibitor of metalloproteinase (TIMP)-1 expression. Lung fibroblasts were treated with 100, 500, and 1,000 microg/ml of Survanta; 10, 50, and 100 microg/ml of SP-A; and 500 microg/ml of Survanta plus 50 microg/ml of SP-A. Growth rate was evaluated by a formazan-based chromogenic assay, apoptosis was evaluated by DNA end labeling and ELISA, and collagen, collagenase-1, and TIMP-1 were evaluated by Northern blotting. Survanta provoked fibroblast apoptosis, induced collagenase-1 expression, and decreased type I collagen affecting mRNA stability approximately 10-fold as assessed with the use of actinomycin D. Collagen synthesis and collagenase activity paralleled the gene expression results. SP-A increased collagen expression approximately 2-fold and had no effect on collagenase-1, TIMP-1, or growth rate. When fibroblasts were exposed to a combination of Survanta plus SP-A, the effects of Survanta were partially reversed. These findings suggest that surfactant lipids may protect against intraluminal fibrogenesis by inducing fibroblast apoptosis and decreasing collagen accumulation.