Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging.

Aging is a key contributor for subclinical progression of late-onset lung diseases. Basal, club, and type II alveolar epithelial cells (AECs) are lung epithelial progenitors whose capacities of differentiation are extensively studied. The timely transition of these cells in response to environmental changes helps maintain the intricate organization of lung structure. However, it remains unclear how aging affects their behavior. This paper demonstrates that the protein expression profiles of a type II AEC marker, prosurfactant protein C (pro-SPC), and a basal cell marker, p63, are altered in the lungs of 14-mo-old versus 7- to 9-wk-old mice. Expression of NH2-terminal-truncated forms of p63 (ΔNp63), a basal cell marker, and claudin-10, a club cell marker, in cytoplasmic extracts of lungs of 14-mo-old mice was upregulated. In contrast, nuclear expression of full-length forms of p63 (TAp63) decreases with age. These alterations in protein expression profiles coincide with dramatic changes in lung functions including compliance. Whole tissue lysates of middle-aged versus aged rhesus monkey lungs display similar age-associated alterations in pro-SPC expression. An age-associated decrease of TAp63 in nuclear lysates was observed in aged monkey group. Moreover, the lungs of 14-mo-old versus 7- to 9-wk-old mice display a wider spreading of ΔNp63-positive CCSP-positive bronchiolar epithelial cells. This expansion did not involve upregulation of Ki67, a representative proliferation marker. Collectively, it is postulated that 1) this expansion is secondary to a transition of progenitor cells committed to club cells from ΔNp63-negative to ΔNp63-positive status, and 2) high levels of cytoplasmic ΔNp63 expression trigger club cell migration.

Update on the Evaluation and Management of Portal Hypertension.

The development of clinically significant portal hypertension (CSPH) in patients with chronic liver disease is an important predictor of varices, variceal hemorrhage, ascites, hepatic encephalopathy, and death. The nomenclature of compensated advanced chronic liver disease, revised from compensated cirrhosis, recognizes the importance of portal hypertension (PH), rather than the histologic finding of cirrhosis, in clinical outcomes. Recent advances in the field have focused on the development of noninvasive methods, including transient elastography (TE), magnetic resonance elastography, and multiparametric magnetic resonance imaging, for predicting PH. TE is evolving to be the most widespread clinical tool to estimate PH, with a liver stiffness (LS) measurement cutoff of greater than or equal to 25 kilopascals (kPa) ruling in CSPH, and that of less than 15 kPa combined with a platelet count of greater than 150 × 109/L ruling out CSPH. Extending utilization of TE to not only LS measurement but also splenic stiffness measurement using the same probes may augment the sensitivity of detecting CSPH and thus selecting candidates warranting endoscopic evaluation for high-risk varices. With respect to management of PH, the role of nonselective ß blockers continues to evolve and may extend beyond variceal bleed in preventing decompensation and development of ascites. Statins have a burgeoning well of data supporting their use, but large, prospective, controlled trials with clinical endpoints are awaited. Further data are still warranted regarding the use of long-term albumin therapy to prevent complications of PH.