Airway mucus hypersecretion is a prominent feature of many obstructive lung diseases. We thus determined the ontogeny and exocytic phenotype of mouse airway mucous cells. In naive mice, ciliated (approximately 40%) and nonciliated (approximately 60%) epithelial cells line the airways, and > 95% of the nonciliated cells are Clara cells that contain Clara cell secretory protein (CCSP). Mucous cells comprise < 5% of the nonciliated cells. After sensitization and a single aerosol antigen challenge, alcian blue-periodic acid Schiff's positive mucous cell numbers increase dramatically, appearing 6 h after challenge (21% of nonciliated/nonbasal cells), peaking from Days 1-7 (99%), and persisting at Day 28 (65%). Throughout the induction and resolution of mucous metaplasia, ciliated and Clara cell numbers identified immunohistochemically change only slightly. Intracellular mucin content peaks at Day 7, and mucin expression is limited specifically to a Clara cell subset in airway generations 2-4 that continue to express CCSP. Functionally, Clara cells are secretory cells that express the regulated exocytic marker Rab3D and, in antigen-challenged mice, rapidly secrete mucin in response to inhaled ATP in a dose-dependent manner. Thus, Clara cells show great plasticity in structure and secretory products, yet have molecular and functional continuity in their identity as specialized apical secretory cells.

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Neutrophil emigration in the lung differs substantially from that in systemic vascular beds where extravasation occurs primarily through postcapillary venules. Migration into the alveolus occurs directly from alveolar capillaries and appears to progress through a sequence of steps uniquely influenced by the cellular anatomy and organization of the alveolar wall. The cascade of adhesive and stimulatory events so critical to the extravasation of neutrophils from postcapillary venules in many tissues is not evident in this setting. Compelling evidence exists for unique cascades of biophysical, adhesive, stimulatory, and guidance factors that arrest neutrophils in the alveolar capillary bed and direct their movement through the endothelium, interstitial space, and alveolar epithelium. A prominent path accessible to the neutrophil appears to be determined by the structural interactions of endothelial cells, interstitial fibroblasts, as well as type I and type II alveolar epithelial cells.

Background-Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a ␤ 2 integrin expressed on human monocytes and a subset of mouse monocytes, has been shown to play a distinct role in human monocyte adhesion on endothelial cells, but the regulation of CD11c in hypercholesterolemia and its role in atherogenesis are unknown. Methods and Results-Mice genetically deficient in CD11c were generated and crossbred with apolipoprotein E (apoE) Ϫ/Ϫ mice to generate CD11c Ϫ/Ϫ /apoE Ϫ/Ϫ mice. Using flow cytometry, we examined CD11c on blood leukocytes in apoE Ϫ/Ϫ hypercholesterolemic mice and found that compared with wild-type and apoE Ϫ/Ϫ mice on a normal diet, apoE Ϫ/Ϫ mice on a Western high-fat diet had increased CD11c ϩ monocytes. Circulating CD11c ϩ monocytes from apoE Ϫ/Ϫ mice fed a high-fat diet exhibited cytoplasmic lipid vacuoles and expressed higher levels of CD11b and CD29. Deficiency of CD11c decreased firm arrest of mouse monocytes on vascular cell adhesion molecule-1 and E-selectin in a shear flow assay, reduced monocyte/macrophage accumulation in atherosclerotic lesions, and decreased atherosclerosis development in apoE Ϫ/Ϫ mice on a high-fat diet. Conclusions-CD11c, which increases on blood monocytes during hypercholesterolemia, plays an important role in monocyte recruitment and atherosclerosis development in an apoE Ϫ/Ϫ mouse model of hypercholesterolemia. Key Words: atherosclerosis Ⅲ cell adhesion molecules Ⅲ leukocytes A therosclerosis associated with hypercholesterolemia is a complex inflammatory process, characterized pathologically by recruitment of monocytic leukocytes in the arterial wall and lipid accumulation in monocytic leukocytes. 1 Monocyte recruitment is a multistep process mediated by adhesion molecules, beginning with rolling, which is mediated by short-lived bonds between E-selectin on endothelial cells (ECs) and sialylated ligands such as P-selectin glycoprotein ligand-1 on monocytes, followed by firm arrest facilitated through interactions between activated ␤ 1 and ␤ 2 integrins on monocytes with vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on ECs. Firmly arrested monocytes subsequently undergo transmigration through other adhesion molecules. 2,3 Therefore, adhesion molecules participating in monocyte-EC interactions play a critical role in atherogenesis. 4 EC activation induced by hypercholesterolemia increases expression of VCAM-1, ICAM-1, and E-selectin, thereby contributing to atherogenesis. 4 -6 However, the effect of hypercholesterolemia on monocyte activation and its contribution to atherogenesis are less defined. Clinical Perspective on p 2717The ␤ 2 integrins, which include CD11a/CD18, CD11b/ CD18, CD11c/CD18, and CD11d/CD18, 7 contribute to atherogenesis as evidenced by a significant reduction in atherosclerosis development in CD18 Ϫ/Ϫ mice, which lack all 4 CD11/CD18 integrins. 4 CD11b has been used as an activation marker for monocytes/macrophages...

Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. While we now know that the androgen receptor (AR) is important for progression to the deadly advanced stages of the disease, it is poorly understood what AR-regulated processes drive this pathology. Here, we demonstrate that AR regulates prostate cancer cell growth via the metabolic sensor 5′-AMP-activated protein kinase (AMPK), a kinase that classically regulates cellular energy homeostasis. In patients, activation of AMPK correlated with prostate cancer progression. Using a combination of radiolabeled assays and emerging metabolomic approaches, we also show that prostate cancer cells respond to androgen treatment by increasing not only rates of glycolysis, as is commonly seen in many cancers, but also glucose and fatty acid oxidation. Importantly, this effect was dependent on androgen-mediated AMPK activity. Our results further indicate that the AMPK-mediated metabolic changes increased intracellular ATP levels and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated mitochondrial biogenesis, affording distinct growth advantages to the prostate cancer cells. Correspondingly, we used outlier analysis to determine that PGC-1α is overexpressed in a subpopulation of clinical cancer samples. This was in contrast to what was observed in immortalized benign human prostate cells and a testosterone-induced rat model of benign prostatic hyperplasia. Taken together, our findings converge to demonstrate that androgens can co-opt the AMPK-PGC-1α signaling cascade, a known homeostatic mechanism, to increase prostate cancer cell growth. The current study points to the potential utility of developing metabolic-targeted therapies directed towards the AMPK-PGC-1α signaling axis for the treatment of prostate cancer.

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complement ͉ differentiation ͉ surfactant proteins ͉ ␣-1-antitrypsin ͉ cystic fibrosis transmembrane conductance receptor T he alveolar epithelium covers Ͼ99% of the internal surface area of the lung and is composed of two major cell types, the alveolar type I (ATI) cell and the alveolar type II (ATII) cell. ATI cells are large flat cells through which exchange of CO 2 /O 2 takes place. They cover Ϸ95% of the alveolar surface and comprise Ϸ40% of the alveolar epithelium and 8% of the peripheral lung cells. In contrast, ATII cells are small, cuboidal cells that cover Ϸ5% of the alveolar surface and comprise 60% of the alveolar epithelium and 15% of the peripheral lung cells. They are characterized by the unique ability to synthesize and secrete surfactant protein C (SPC) and by the distinct morphological appearance of inclusion bodies, known as lamellar bodies. Important functions of ATII cells are (i) to synthesize, store, and secrete surfactant, which reduces surface tension, preventing collapse of the alveolus; (ii) to transport ions from the alveolar fluid into the interstitium, thereby minimizing alveolar fluid and maximizing gas exchange; (iii) to serve as progenitor cells for ATI cells, which is particularly important during reepithelialization of the alveolus after lung injury; and (iv) to provide pulmonary host defense by synthesizing and secreting several complement proteins including C3 and C5

Beginning in the first 60 minutes after reperfusion, C5a, TGF-beta 1, and MCP-1, acting sequentially, promote infiltration of monocytes into formerly ischemic myocardium. These events may promote the healing of myocardial injury facilitated by reperfusion.