Abstract
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
Smoking Increases Osteopontin Expression in the Lung
Macrophages and Langerhans cells accumulate in fibrotic tissues of patients with smoking-related interstitial lung diseases. To determine whether osteopontin, a chemotactic agent for both macrophages and Langerhans cells, mediates cell recruitment in smokers, Prasse et al (Am J Pathol 2009, 174: 1683–1691) compared osteopontin levels in bronchoalveolar lavage from smokers with diverse interstitial lung diseases, healthy smokers, and healthy nonsmokers. They found high levels of osteopontin expression in patients with pulmonary Langerhans cell histocytosis and desquamative interstitial pneumonitis, whereas healthy smokers had lower levels, and healthy nonsmokers produced no osteopontin. Osteopontin expression in alveolar macrophages could be stimulated by nicotine treatment. In addition, osteopontin overexpression in rat lung resulted in recruitment of macrophages and Langerhans cells, resulting in symptoms similar to pulmonary Langerhans cell histocytosis. These results indicate that osteopontin may be pathogenic in smoking-initiated lung disease.
Notch1 Signaling Contributes to Lung Fibrosis
An increase in the number of myofibroblasts contributes to the extracellular matrix and fibrogenic cytokine production that characterizes progressive pulmonary fibrosis. FIZZ1 (found in inflammatory zone 1) can induce myofibroblast differentiation during pulmonary fibrosis without affecting cell proliferation. Liu et al (Am J Pathol 2009, 174: 1745–1755) hypothesized that Notch1, which regulates cell fate in numerous cell types, plays a role in FIZZ1-mediated myofibroblast differentiation. They found that the activated intracellular domain of Notch1 (NIC) increased expression of α-smooth muscle actin in fibroblasts and that mice with deficient Notch1 signaling had decreased responses to FIZZ1 and impaired lung fibrosis. Taken together, these data suggest a role for Notch1 signaling in response to FIZZ1 during myofibroblast differentiation and provide a novel target for treatment of pulmonary fibrosis.
SPARC (Secreted Protein Acidic and Rich in Cysteine) in Glomerular Disease
Chronic glomerular disease is associated with significant podocyte injury and loss. SPARC, a counteradhesive protein, is up-regulated in podocytes on injury. To define the role of SPARC in glomerular disease, Sussman et al (Am J Pathol 2009, 174: 1827–1836) examined nephrotoxic nephritis in mice deficient in SPARC as well as in normal mice. They found that glomerulosclerosis was reduced in SPARC-null mice compared with normal controls, in part because of maintenance of podocytes. In addition, SPARC-deficient podocytes were more resistant to stress-induced detachment. These results indicate that SPARC may play an instigating role in podocyte detachment and glomerulosclerosis.
Gangliosides May Protect Against Parkinson’s Disease
Accumulation of α-synuclein is pathogenic in Parkinson’s disease and other synucleopathies, such as dementia with Lewy bodies (DLB) and multisystem atrophy. Gangliosides, such as GM1, have been shown to inhibit α-synuclein aggregation. To elucidate the mechanism that drives ganglioside-mediated protection of synucleopathies, Wei et al (Am J Pathol 2009, 174: 1891–1909) treated DLB-linked neuroblastoma cells with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase. These PDMP-treated cells developed lysosomal disease characterized by reduced lysosomal activity, enhanced lysosomal membrane permeability, and decreased expression of lysosomal membrane proteins. PDMP-mediated inhibition of the autophagy-lysosomal pathway resulted in both accumulation of α- and β-synucleins and cellular cytotoxicity. Ganglioside treatment reversed this phenotype, suggesting that gangliosides protect against the lysosomal pathology of synucleopathies.
Suppressor of Cytokine Signaling (SOCS)-1 Inhibits Prostate Cancer Growth
SOCS family members are expressed in a variety of cancers, including chronic myeloid leukemia, melanoma, and prostate cancer. The role of the various SOCS family members in carcinogenesis, however, may be tissue-dependent. Neuwirt et al (Am J Pathol 2009, 174: 1921–1930) identified SOCS-1 expression in multiple prostate cancer cell lines as well as in tissues from prostate cancer patients. They found that SOCS-1 expression was up-regulated in response to interleukin-6 or androgen therapy and that inhibition of SOCS-1 expression stimulated tumor cell growth through the activation of cyclins and cyclin-dependent kinases. SOCS-1, therefore, plays a negative regulatory role in prostate cancer proliferation.
TIP30 Inhibits Lung Cancer Metastasis
TIP30 is a putative tumor suppressor with decreased expression in numerous cancers including melanoma, breast cancer, and colon cancer. To determine whether TIP30 plays a role in lung cancer progression and metastasis, Tong et al (Am J Pathol 2009, 174: 1931–1939) examined TIP30 expression in paired cancerous and noncancerous lung tissue. TIP30 expression was decreased in a third of non-small cell lung cancers compared with normal controls, and reduced TIP30 expression correlated with lymph node metastasis. In addition, inhibition of TIP30 expression promoted lung cancer metastasis and angiogenesis in mice, possibly because of increased levels of osteopontin, matrix metalloproteinase-2, and vascular endothelial growth factor. These findings highlight TIP30 as a potential new therapeutic for metastatic lung cancer.