Synapses let loose for a change: inhibitory synapse pruning throughout experience-dependent cortical plasticity

In this issue of Neuron, Chen et?al. (2012) and van Versendaal et?al. (2012) used fluorescently tagged gephyrin to track inhibitory synapses in the mouse visual cortex in?vivo. Their studies show that visual experience-dependent plasticity is associated with clustered and location-specific pruning of inhibitory synapses.     

Bronchial wedge pressure in experimental pulmonary emphysema]

The work of breathing and its subdivisions, pulmonary compliance, the bronchial wedge pressure, intrapleural and esophageal pressures were measured in 8 normal rabbits and in 15 rabbits with emphysema induced by intravenous injections of licopodium spores. Investigations were carried out under intravenous thiopenthal anesthesia. In normal rabbits the amplitude of the bronchial wedge pressure was on the average twice as great as the pleural and esophageal pressures.     

Biochemical links between cigarette smoking and pulmonary emphysema

A large body of circumstantial evidence has accumulated in the last 20 yr, suggesting that alveolar effacement in pulmonary emphysema is due to unrestrained proteolytic (elastolytic) activity in lung connective tissue. Even though this hypothesis still requires rigorous proof, newer information is rapidly developing that links the protease-pathogenesis model to the primary environmental risk factor associated with the disease, namely cigarette smoking. A triad of chemical and cellular effects produced by cigarette smoke have been suggested as factors contributing to altered elastin metabolism and eventual development of emphysema in smokers. The present article reviews some of these observations, seeks to place them within the overall framework of the protease model, and attempts to raise questions for future study.     

Effect of pulmonary emphysema on diaphragm capillary geometry

Poole, David C., and Odile Mathieu-Costello. Effect ofpulmonary emphysema on diaphragm capillary geometry.J. Appl. Physiol. 82(2): 599-606, 1997.In emphysema, the diaphragm shortens by losing sarcomeres. Wehypothesized that unless capillaries undergo a similar shortening,capillary geometry must be altered. Without quantifying this geometry,capillary length and surface area per fiber volume, which are criticalmeasurements of the structural potential for blood-tissue exchange,cannot be resolved. Five months after intratracheal elastase (E) orsaline (control; C) instillation, diaphragms from male Syrian goldenhamsters were glutaraldehyde perfusion fixed in situ at reference lungpositions (residual volume, functional residual capacity, total lungcapacity) to provide diaphragms fixed over a range of sarcomerelengths. Subsequently, diaphragms were processed for electronmicroscopy and analyzed morphometrically. Emphysema increased lungvolume changes from 20 to 25 cmH₂O airway pressure (i.e.,passive vital capacity) and excised lung volume (bothP < 0.001). In each region of thecostal diaphragm (i.e., ventral, medial, dorsal), sarcomere number wasreduced (all P < 0.05).Capillary-to-fiber ratio increased (C = 2.2 ± 0.1, E = 2.8 ± 0.1; P < 0.01) and fibershypertrophied (C = 815 ± 35, E = 987 ± 67 µm²;P < 0.05; both values at 2.5 µmsarcomere length). Capillary geometry was markedly altered by the lossof sarcomeres in series. Specifically, the additional capillary lengthderived from capillary tortuosity and branching was increased by 183%at 2.5 µm sarcomere length compared with C values (C, 359 ± 43;E, 1,020 ± 158 mm²,P < 0.01). This significantlyincreased total capillary length (C, 3,115 ± 173; E, 3,851 ± 219 mm² at 2.5 µm,P < 0.05) and surface area (C, 456 ± 13; E, 519 ± 24 cm¹,P < 0.05) per fiber volume. Thusemphysema substantially alters diaphragm capillary geometry andaugments the capillary length and surface area available forblood-tissue exchange.

     

Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice

Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg x kg(-1) x day(-1) KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2alpha) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice.     

Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema.

Protease-antiprotease imbalance due to genetic variation may be responsible for the development of pulmonary emphysema induced by smoking. Since matrix metalloproteinases (MMPs) have recently been suggested to play important roles in the pathogenesis of pulmonary emphysema, the association between the functional polymorphism of MMP-9 (-1562C/T) and the development of pulmonary emphysema was examined in 110 smokers and 94 nonsmokers in Japan. The T allele frequency was higher in subjects with distinct emphysema on chest CT-scans (n = 45) than in those without it (n = 65) (0.244 vs 0.123, P = 0.02). Logistic regression analysis demonstrated that the T allele is a risk factor for smoking-induced emphysema (odds ratio = 2.69, P = 0.02). DL(CO)/VA was lower (P = 0.02) and emphysematous changes were more conspicuous (P = 0.03) in subjects with C/T or T/T (n = 35) than in those with C/C (n = 75). These results suggest that the polymorphism of MMP-9 acts as a genetic factor for the development of smoking-induced pulmonary emphysema.