Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma.

Asthma is an increasingly common disorder responsible for considerable morbidity and mortality. Although obesity is a risk factor for asthma and weight loss can improve symptoms, many patients do not adhere to low calorie diets and the impact of dietary restriction on the disease process is unknown. A study was designed to determine if overweight asthma patients would adhere to an alternate day calorie restriction (ADCR) dietary regimen, and to establish the effects of the diet on their symptoms, pulmonary function and markers of oxidative stress, and inflammation. Ten subjects with BMI>30 were maintained for 8 weeks on a dietary regimen in which they ate ad libitum every other day, while consuming less than 20% of their normal calorie intake on the intervening days. At baseline, and at designated time points during the 8-week study, asthma control, symptoms, and Quality of Life questionnaires (ACQ, ASUI, mini-AQLQ) were assessed and blood was collected for analyses of markers of general health, oxidative stress, and inflammation. Peak expiratory flow (PEF) was measured daily on awakening. Pre- and postbronchodilator spirometry was obtained at baseline and 8 weeks. Nine of the subjects adhered to the diet and lost an average of 8% of their initial weight during the study. Their asthma-related symptoms, control, and QOL improved significantly, and PEF increased significantly, within 2 weeks of diet initiation; these changes persisted for the duration of the study. Spirometry was unaffected by ADCR. Levels of serum beta-hydroxybutyrate were increased and levels of leptin were decreased on CR days, indicating a shift in energy metabolism toward utilization of fatty acids and confirming compliance with the diet. The improved clinical findings were associated with decreased levels of serum cholesterol and triglycerides, striking reductions in markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts), and increased levels of the antioxidant uric acid. Indicators of inflammation, including serum tumor necrosis factor-alpha and brain-derived neurotrophic factor, were also significantly decreased by ADCR. Compliance with the ADCR diet was high, symptoms and pulmonary function improved, and oxidative stress and inflammation declined in response to the dietary intervention. These findings demonstrate rapid and sustained beneficial effects of ADCR on the underlying disease process in subjects with asthma, suggesting a novel approach for therapeutic intervention in this disorder.

Inferior vena caval filters: key considerations.

Surgical interruption of the inferior vena cava (IVC) as a means to prevent pulmonary embolism and its consequences has been entertained since the end of the 19th century. Initial methods were crude, however, but their deficiencies led to the development of newer techniques. Despite increasing indications and use of permanent IVC filters there remains controversy regarding their efficacy and complications. The purpose of this article is to review the pertinent literature and, it is hoped, aid in the development of a rational approach to the use of IVC filters. The evolving data regarding the retrievable filters are also discussed.

The granulopoietic cytokine response and enhancement of granulopoiesis in mice during endotoxemia.

In response to bacterial infection, the production of neutrophils by the bone marrow is accelerated. This study investigated the granulopoietic cytokine response and granulopoiesis during endotoxemia. Male Balb/c mice were intravenously challenged with lipopolysaccharide (LPS, 20 microg in 100 microL of saline per mouse). Control animals received saline alone. In a separate set of experiments, i.v. murine granulocyte colony-stimulating factor (G-CSF; 20 microg/kg) or vehicle (5% dextrose) was administered to mice. Endotoxemia caused a marked increase in G-CSF, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein-2 (MIP-2) in the plasma and bone marrow between 1 and 4 h after the challenge. G-CSF, KC, and MIP-2 mRNA expression was also upregulated in the lung, liver, spleen, and bone marrow between 1 and 4 h after i.v. LPS. Intravenous administration of G-CSF caused a significant increase in G-CSF concentration in the plasma and bone marrow without upregulating G-CSF mRNA expression in the bone marrow. The levels of phospho-signal transducers and activators of transcription 3 and phospho-p44/42 mitogen-activated protein kinase were elevated in bone marrow cells at 30 min and 4 h after i.v. G-CSF and LPS, respectively. Granulocyte-macrophage colony-forming unit counts were significantly increased in the bone marrow, spleen, and blood at 48 h post-i.v. LPS or G-CSF. These data show that extramedullary organs produce granulopoietic cytokines in response to LPS. Because the tissue mass in extramedullary organs far exceeds that in the bone marrow, extramedullary production of these cytokines likely play a critical role in the regulation of the host's granulopoietic response to endotoxemia.

Pectus excavatum with inspiratory inferior vena cava compression: a new presentation of pulsus paradoxus.

A 29-year-old man with pectus excavatum presented with exercise intolerance, pulsus paradoxus, and paradoxically split S2. Chest computed tomography (CT) showed the heart shifted leftward and a pectus severity index of 7.18. Cardiopulmonary exercise study showed reduced VO2max, anaerobic threshold, and oxygen pulse. Echocardiography revealed a decline in mitral and tricuspid valve inflow, and stroke volume during inspiration. Cardiac extrinsic compression and anatomic cardiac abnormalities were not present. Dynamic magnetic resonance imaging (MRI) demonstrated inspiratory inferior vena cava (IVC) compression at the diaphragm. We discuss IVC compression by the diaphragm as a source of patient symptoms and as a mechanism for pulsus paradoxus associated with pectus excavatum.

The lung in sepsis: fueling the fire.

Advances in our understanding of the molecular mechanisms underlying the pathophysiology of sepsis have generated considerable efforts in manipulating the host response during this frequently lethal condition. While existing trials of immune modulation have been largely unsuccessful, an appreciation for the roles of individual organ systems in sepsis is important to enable clinicians to discern how each functions as both a target for injury and a contributor to the derangement in homeostasis seen in sepsis. Such awareness will encourage treatment decisions aimed at optimizing conventional therapy while minimizing the adverse effects of supportive care, and it may also guide the incorporation of newer immunomodulatory therapeutics into our existing modalities. This article discusses the lung's response to sepsis, from the standpoint of organ dysfunction related to sepsis as well as its participation in the generation and maintenance of the systemic inflammatory state.

Interferon-gamma enhances the pulmonary CXC chemokine response to intratracheal lipopolysaccharide challenge.

CXC chemokines are major chemoattractants for pulmonary polymorphonuclear leukocyte (PMNL) recruitment. To study the effects of interferon (IFN)-gamma on the pulmonary chemokine response to lipopolysaccharide (LPS) challenge, rats were treated with intratracheal IFN-gamma (1x10(5) U/rat) 24 h before an intratracheal LPS (100 microg/rat) challenge. Intratracheal LPS caused significant increases in both cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 in bronchoalveolar lavage (BAL) fluid and pulmonary PMNL recruitment. IFN-gamma enhanced these responses. IFN-gamma also increased LPS-induced tumor necrosis factor (TNF)-alpha in BAL fluid. LPS-induced TNF-alpha and CINC mRNA expression in alveolar macrophages was increased by IFN-gamma. CD11b/c and CD18 expression on circulating PMNLs was not affected by IFN-gamma, nor was the chemotaxis of these cells. IFN-gamma increases the pulmonary CXC chemokine response, which may serve as one mechanism underlying enhanced PMNL delivery into the lung.

Neutrophil modulation of the pulmonary chemokine response to lipopolysaccharide.

When cells within the intrapulmonary compartment are exposed to pathogens or their products such as lipopolysaccharide, they produce CXC chemokines in order to attract circulating neutrophils into the lower respiratory tract. Previous studies have shown that as neutrophils (PMNs) enter the lung, bronchoalveolar lavage (BAL) chemokine levels are decreased. In this study, we determined the intrapulmonary and systemic responses to two important rat chemokines, cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2), to intratracheal (i.t.) LPS (100 microg in 0.5 mL of phosphate-buffered saline) under neutropenic (cyclophosphamide [CPA]) and neutrophilic (G-CSF) conditions. By 4 h after i.t. LPS, CPA pretreatment decreased PMN recruitment 83% and G-CSF increased PMN recruitment 91% compared with recruitment into the lung in vehicle-pretreated rats (42.7 +/- 19.3 million PMNs). Neutropenic rats had increased CINC and MIP-2 concentrations in BAL fluid 4 h after i.t. LPS when compared with levels seen in vehicle controls (P < 0.05). In vitro LPS-stimulated chemokine production by alveolar macrophages obtained from CPA- and vehicle-pretreated animals did not differ. The increase in BAL fluid chemokine levels in neutropenic rats corresponded to increased chemotaxis of neutrophils to BAL fluid from CPA-pretreated rats as compared with the chemotaxis response of PMN to BAL fluid from vehicle-pretreated rats. In contrast, G-CSF enhancement of neutrophil recruitment decreased chemotactic activity of BAL fluid collected 4 h after i.t. LPS. These data show that as neutrophils are recruited into the lung, they alter chemokine levels, which most likely serves to down-regulate the inflammatory response.

Pulmonary host defenses and alcohol.

Alcohol abuse is a major risk factor for the development of many infectious diseases, particularly pulmonary infections. Bacterial pneumonia and other lung infections in alcohol-abusing patients are usually severe and associated with a high morbidity and mortality. Normal host defense mechanisms in the respiratory tract consist of both innate and acquired immunity which operate effectively in preventing the invasion of infectious pathogens. Numerous in vivo and in vitro studies have shown that alcohol is an immunosuppressive agent that compromises the function of various components of the immune defense system. In recent years, human immunodeficiency virus infection has become epidemic, especially in individuals who abuse alcohol and other substances. Treatment of pulmonary infections in these immunocompromised hosts has continued to be a major challenge in our health care system. Immunotherapy to improve or enhance pulmonary host defense function in conjunction with aggressive antimicrobial regimens may provide a new approach in the management of infections in these patients.

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension.

OBJECTIVES: The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND: Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS: Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS: During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS: Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Compartmentalization of macrophage inflammatory protein-2, but not cytokine-induced neutrophil chemoattractant, in rats challenged with intratracheal endotoxin.

An important feature of the pulmonary inflammatory response is that the production of certain cytokines and chemokines is largely confined to the lung. This study investigated the local and systemic responses of macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) in rats administered with either intratracheal or intravenous lipopolysaccharide (LPS). Intratracheal LPS induced a significant increase in MIP-2 in bronchoalveolar lavage (BAL) fluid with no detectable MIP-2 in the plasma. In contrast, CINC was significantly increased in both BAL fluid and the plasma after intratracheal LPS challenge. Cell-associated MIP-2 was increased in the pulmonary-recruited neutrophils (PMNs) but not in the circulating PMNs in rats given intratracheal LPS. Cell-associated CINC was increased in both the recruited and circulating PMNs in these animals. Intravenous LPS caused a marked increase in plasma MIP-2 and CINC, whereas only a small elevation of both MIP-2 and CINC concentrations in BAL fluid was observed. The lack of CINC compartmentalization compared to MIP-2 implies that these C-X-C chemokines are regulated differentially and may have different effects upon polymorphonuclear leukocyte (PMN) recruitment into the alveolar space in response to intrapulmonary LPS or bacterial challenge.

Acute alcohol intoxication suppresses the CXC chemokine response during endotoxemia.

BACKGROUND: CXC chemokines play an important role in host defense against infections. Alcohol is a frequently abused drug that inhibits numerous immune functions of the host. This study investigated the effects of alcohol on CXC chemokine macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) responses in rats challenged with intravenous lipopolysaccharide (LPS). METHODS: Acute ethanol intoxication was induced by an intraperitoneal injection of 20% alcohol (5.5 g/kg). Thirty minutes thereafter, LPS (500 microg/kg) was administered intravenously. In another set of experiments, rats were intravenously administered an anti-tumor necrosis factor-alpha (TNFalpha) neutralizing antibody (10 mg per rat) 2 hr before the LPS challenge. RESULTS: At 1 and 2 hr after the LPS challenge, MIP-2, CINC, and TNFalpha concentrations in the plasma were significantly increased. Alcohol intoxication suppressed the MIP-2, CINC, and TNFalpha responses in the bloodstream during endotoxemia. Alcohol also suppressed the increase in plasma chemotactic activity and polymorphonuclear leukocyte adhesion molecule expression in rats with endotoxemia. MIP-2 and CINC messenger RNA (mRNA) expression was significantly increased 1 hr after endotoxemia in the lung, liver, and spleen. Alcohol suppressed the up-regulation of MIP-2 mRNA expression in all of these organs and CINC mRNA expression in the lungs of rats with endotoxemia. TNFalpha neutralization minimally inhibited plasma CINC and MIP-2 responses during endotoxemia and did not suppress the increase in plasma chemotactic activity. CONCLUSIONS: These results show that alcohol suppresses the systemic CXC chemokine response to LPS, which is not primarily mediated by ethanol-induced suppression of TNFalpha. This disruption of host-defense function may serve as one mechanism underlying the increased risk of infectious diseases in hosts who abuse alcohol.