Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models.

The cellular mechanisms that result in the initiation and progression of emphysema are clearly complex. A growing body of human data combined with discoveries from mouse models utilizing cigarette smoke exposure or protease administration have improved our understanding of emphysema development by implicating specific cell types that may be important for the pathophysiology of chronic obstructive pulmonary disease. The most important aspects of emphysematous damage appear to be oxidative or protease stress and sustained macrophage activation and infiltration of other immune cells leading to epithelial damage and cell death. Despite the identification of these associated processes and cell types in many experimental studies, the reasons why cigarette smoke and other pollutants result in unremitting damage instead of injury resolution are still uncertain. We propose an important role for macrophages in the sequence of events that lead and maintain this chronic tissue pathologic process in emphysema. This model involves chronic activation of macrophage subtypes that precludes proper healing of the lung. Further elucidation of the cross-talk between epithelial cells that release damage-associated signals and the cellular immune effectors that respond to these cues is a critical step in the development of novel therapeutics that can restore proper lung structure and function to those afflicted with emphysema.

Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans.

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes.

Endovascular management of iliac rupture during endovascular aneurysm repair.

BACKGROUND: Inadequate iliac artery diameter, calcification, and tortuosity are associated with increased incidence of iliac injury during abdominal (EVAR) and thoracic endovascular aneurysm repair (TEVAR). Despite careful preoperative assessment and use of iliac conduits, inadvertent iliac rupture is a source of morbidity and mortality. This report details our single-center, 10-year experience with intraoperative iliac artery rupture and describes a successful endovascular salvage technique. METHODS: All patients undergoing EVAR and TEVAR between August 1997 and June 2008 were reviewed. Computed tomography (CT) measurements of access vessels were obtained for all patients. The smallest diameter of the external or common iliac artery was used to determine suitability for access based on the instructions for use for each device. Patients who underwent repair of a procedure-related iliac artery rupture were identified. Outcomes among patients who did not have an access vessel rupture (nonruptured group) and those who did (ruptured group) were compared. Patency of the endovascular iliac repair is reported. RESULTS: During the study period, 369 EVARs and 67 TEVARs were performed. Eleven iliac conduits were used, all during TEVAR (16%). There were 18 ruptured iliac arteries in 17 patients; 11 EVAR patients (2.98%) sustained iliac rupture vs six TEVAR patients (8.9%). One EVAR patient was converted to open repair. Seventeen ruptures in 16 patients were successfully treated with endovascular stent graft placement. Iliac rupture was more likely to occur during TEVAR (8.9%) than EVAR (2.98%; P = .0239, Fisher exact test). Significantly more women were in the ruptured group (76% vs 19%; P < .0001, Fisher exact test). Patients in the ruptured group had longer lengths of stay (7.6 vs 5.1 days; P = .0895, t test), no 30-day mortality, but a procedure-related mortality of 11.8%. In the nonrupture group, 30-day mortality was 6.6% (4 of 61) and 2.8% (10 of 358) for TEVAR and EVAR, respectively, and procedure-related mortality was 9.8% (6 of 61) and 3.1% (11 of 358). For endovascular repair of iliac rupture, primary and primary-assisted patency was 88.2% and 94.1%, respectively, with median follow-up of 40 months (range 10-115 months). CONCLUSION: Iliac rupture during EVAR or TEVAR can be successfully managed with endovascular stent grafting. Higher mortality and length of stay associated with iliac artery rupture confirm that there is no substitute for prevention. Access vessels of all patients undergoing EVAR should be examined closely for suitability. The threshold for using an iliac conduit, especially in women undergoing TEVAR, should be low.

Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria.

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.

Minimally invasive repair of fenestrated atrial septal aneurysm.

BACKGROUND: Atrial septal aneurysms (ASAs) are uncommon but are associated with significant embolic morbidity when an interatrial communication is present. Although surgical reconstruction has traditionally been approached through a median sternotomy, minimally invasive techniques may be employed to reduce pain and recovery time. METHODS: We present a video-assisted technique via right inframammary minithoracotomy utilizing peripheral cannulation for cardiopulmonary bypass. Included is a discussion of surgical tips, potential pitfalls and a description of unique technical aspects that differentiate atrial septal repair from other minimally invasive cardiac operations. RESULTS: A complete repair of the defect was confirmed by intraoperative transesophageal echocardiography (TEE). The patient made an uncomplicated recovery and was discharged home within 48 hours of surgery. CONCLUSIONS: Minimally invasive repair of an ASA utilizing peripheral cannulation for cardiopulmonary bypass and a right inframammary incision can be accomplished with satisfactory technical success and recovery time.

Recruited monocytes modulate malaria-induced lung injury through CD36-mediated clearance of sequestered infected erythrocytes.

Pulmonary complications occur in a significant percentage of adults and children during the course of severe malaria. The cellular and molecular innate immune mechanisms that limit the extent of pulmonary inflammation and preserve lung function during severe Plasmodium infections remain unclear. In particular, the contributions to pulmonary complications by parasitized erythrocyte sequestration and subsequent clearance from the lung microvasculature by immune cells have not been clearly defined. We used the Plasmodium berghei ANKA-C57BL/6 mouse model of severe malaria to investigate the mechanisms governing the nature and extent of malaria-associated lung injury. We have demonstrated that sequestration of infected erythrocytes on postcapillary endothelial surfaces results in acute lung injury and the rapid recruitment of CCR2(+)CD11b(+)Ly6C(hi) monocytes from the circulation. These recruited cells remain in the lungs as monocyte-derived macrophages and are instrumental in the phagocytic clearance of adherent Plasmodium berghei-infected erythrocytes. In contrast, alveolar macrophages do not play a significant role in the clearance of malaria-infected cells. Furthermore, the results obtained from Ccr2(-/-), Cd36(-/-), and CD36 bone marrow chimeric mice showed that sequestration in the absence of CD36-mediated phagocytic clearance by monocytes leads to exaggerated lung pathologic features. In summary, our data indicate that the intensity of malaria-induced lung pathologic features is proportional to the steady-state levels of Plasmodium-infected erythrocytes adhering to the pulmonary vasculature. Moreover, the present work has defined a major role of recruited monocytes in clearing infected erythrocytes from the pulmonary interstitium, thus minimizing lung damage.

Study of complexation in methanol/water mixtures by infrared and Raman spectroscopy and multivariate curve resolution-alternating least-squares analysis.

The structure of the mobile phase in liquid chromatography plays an important role in the determination of retention behavior on reversed-phase stationary materials. One of the most commonly employed mobile phases is a mixture of methanol and water. In this work, infrared and Raman spectroscopic methods were used to investigate the structure of species formed in methanol/water mixtures. Chemometric methods using multivariate curve resolution by alternating least-squares analysis were used to resolve the overlapped spectra and to determine concentration profiles as a function of composition. The results showed that the structure of these mixtures could be described by a mixture model consisting of four species, namely, methanol, water, and two complexes, methanol/water (1:1) and methanol/water (1:4). The spectral frequencies and concentration profiles found from the Raman and infrared measurements were consistent with one another and with theoretical calculations.