Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease

Abstract

Objectives-Reduced caveolin-1 levels in scleroderma lung fibroblasts and the lungs of bleomycin-treated mice promote collagen overexpression and lung fibrosis. We now evaluate whether caveolin-1 is deficient in leucocytes from bleomycin-treated mice and scleroderma patients and examine the consequences of this deficiency and its reversal.Methods-Mice or cells received the caveolin-1 scaffolding domain (CSD) peptide to reverse the pathological effects of reduced caveolin-1 expression. In bleomycin-treated mice, we examined caveolin-1 levels in leucocytes and the effect of CSD peptide on leucocyte accumulation in lung tissue. To validate our results in human disease and identify caveolin-1-regulated molecular mechanisms, we isolated monocytes and neutrophils from scleroderma patients and control subjects and evaluated caveolin-1, ERK, JNK, p38, CXCR4, and MMP-9 expression/activation. We also studied these parameters in monocytes treated with cytokines or CSD peptide.Results-Leucocyte caveolin-1 is important in lung fibrosis. In bleomycin-treated mice, caveolin-1 expression is diminished in monocytes and CSD peptide inhibits leucocyte recruitment into the lungs. These observations are relevant to human disease. Scleroderma monocytes and neutrophils contain less caveolin-1 and more activated ERK, JNK, and p38 than their normal counterparts. CSD peptide treatment reverses ERK, JNK, and p38 hyperactivation. Scleroderma monocytes also overexpress CXCR4 and MMP-9. The overexpression of CXCR4 and MMP-9 is inhibited by the CSD peptide. Cytokine treatment of normal monocytes causes adoption of the scleroderma phenotype: low caveolin-1, high CXCR4 and MMP-9, and signaling molecule hyperactivation.Conclusions-Caveolin-1 downregulation in leucocytes contributes to fibrotic lung disease, highlighting caveolin-1 as a promising therapeutic target in scleroderma.

Caveolin-1: a critical regulator of lung injury

“…Wang et al (111) and Tourkina et al (102) reported marked reduction in cav-1 expression in lung tissues or monocytes/neutrophils from patients with idiopathic pulmonary fibrosis or scleroderma, respectively, compared with controls (102,103,111). Moreover, Tourkina et al demonstrated the potential role of cav-1 as a lung-protective protein by using the cav-1 CSD peptide to treat scleroderma/fibrosis (102,103,111).…”

Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease

“…Ten-week-old, male CD1 mice (Charles River Laboratories, Boston, MA) maintained under pathogen-free conditions were treated with bleomycin (Teva Parenteral Medicines, Irvine, CA) by the "direct model" as previously described (26) or the "pump model." In the pump model, osmotic minipumps (ALZET 1007D; DURECT, Cupertino, CA) containing either 100 l saline vehicle or bleomycin (100 U/kg) designed to deliver their contents at 0.5 l/h for 7 days were implanted under isofluorane anesthesia under the loose skin on the back of the mice slightly posterior to the scapulae.…”

Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis

“…It has previously been reported that the expression of CAV1 is decreased in tissues and peripheral blood mononuclear cells of patients with SSc 11 12 22. In addition, CAV1 knockout mice develop progressive tissue fibrosis resembling that found in human SSc 9 11 23.…”

“…Numerous studies published during the past decade have provided strong evidence that CAV1 participates in the pathogenesis of fibrotic diseases through regulation of TGFβ receptor internalisation and degradation, effectively decreasing or abolishing TGFβ signalling with a resultant antifibrotic effect 9. Indeed, a reduction in CAV1 expression has been reported in affected skin, lungs and peripheral blood cells of patients with SSc, and CAV1-deficient mice spontaneously develop progressive tissue fibrosis 11 12. Moreover, decreased expression of CAV1 has also been reported in other human fibrotic disorders 13 14…”