Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca 2؉ current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.The endoplasmic reticulum (ER) provides a folding environment for newly synthesized secretory and membrane proteins (10). Aberrant protein folding due to extracellular stimuli, such as ischemia and oxidative stress, and genetic mutation lead to the accumulation of misfolded proteins in the ER, which in turn evokes the unfolded protein response (43), which reduces the amount of misfolded proteins by inducing the production of ER chaperones that promote protein folding, reducing general protein synthesis (16) and enhancing the degradation of misfolded proteins via a ubiquitin-proteasome system termed ER-associated degradation (7, 9, 60). The persistent accumulation of misfolded proteins beyond the capacity of ER quality control causes cellular dysfunction and cell death (24,25,46). This process is involved in diverse human disorders, including diabetes mellitus (14, 42) and neurodegenerative diseases such as Alzheimer's (23) and Parkinson's (20).Misfolded proteins had been believed to remain in the ER, but recent genetic analyses in Saccharomyces cerevisiae have indicated that the unfolded protein response involves the whole secretory pathway (56) and that some misfolded proteins require transport between the ER and the Golgi complex for ER-associated degradation (17,41,53,58). In addition, certain misfolded proteins in mammalian cells have also been reported to exit the ER and recycle between the ER and post-ER compartments, associating with ER chaperones. The KDEL receptor mediates this retrieval, suggesting that the secretion of misfolded proteins from the ER and their retrieval may contribute to ER quality control (12, 62).The KDEL receptor has been identified as a retrieval receptor for luminal ER chaperones that have a carboxyl-te...

We assessed in eight dogs the accuracy with which electrical impedance tomography (EIT) can monitor changes in lung volume by comparing the changes in mean lung conductivity obtained with EIT to changes in esophageal pressure (Pes) and to airway opening pressure (Pao) measured after airway occlusion. The average volume measurement errors were determined: 26 ml for EIT; 35 ml for Pao; and 54 ml for Pes. Subsequently, lung inflation due to applied positive end-expiratory pressure was measured by EIT (delta VEIT) and Pao (delta VPAO) under both inflation and deflation conditions. Whereas delta VPAO was equal under both conditions, delta VEIT was 28 ml greater during deflation than inflation, indicating that EIT is sensitive to lung volume history. The average inflation delta VEIT was 67.7 +/- 78 ml greater than delta VPAO, for an average volume increase of 418 ml. Lung inflation due to external expiratory resistance was measured during ventilation by EIT (delta VEIT,vent) and Pes (delta VPes,vent) and at occlusion by EIT (delta VEIT,occl), Pes, and Pao. The average differences between EIT estimates and delta VEIT,occl were 5.8 +/- 44 ml for delta VEIT,vent and 49.5 +/- 34 ml for delta VEIT,occl. The average volume increase for all dogs was 442.2 ml. These results show that EIT can provide usefully accurate estimates of changes in lung volume over an extended time period and that the technique has promise as a means of conveniently and noninvasively monitoring lung hyperinflation.

When isolated constricted airway smooth muscle is oscillated, muscle tone decreases. We investigated whether changing tidal volume (VT) would affect induced bronchoconstriction in an in vivo canine model. Open-chest dogs were intubated with a double-lumen endotracheal tube, which isolated each main bronchus, and mechanically ventilated with a dual-cylinder ventilator. Bronchial pressure (Pbr) and flow were measured separately in each lung. Resistance and elastance were calculated by fitting the changes in Pbr, flow, and volume to the equation of motion. After baseline measurements at the same VT (150 ml), the two lungs were ventilated with different VT (50 vs. 250 ml) at a constant positive end-expiratory pressure. A continuous infusion of methacholine was begun, and measurements were repeated. The two lungs were then ventilated with the same VT (250 ml), and measurements were again repeated. A similar protocol was performed in a second group of dogs in which mean Pbr was kept constant. Bronchoconstriction was more severe in the lung ventilated with lower VT in both protocols. When VT was reset to the same amplitude in the two lungs, the difference in bronchoconstriction was abrogated. These results demonstrate that large VT inhibits airway smooth muscle contraction, regardless of mean Pbr.