Mechanical ventilation has been shown to produce lung injury characterized by noncardiogenic pulmonary edema. Keratinocyte growth factor (KGF) is a heparin-binding growth factor that causes alveolar ...type II pneumocyte hyperplasia. KGF pretreatment and the resultant pneumocyte hyperplasia reduce fluid flux in models of lung injury. We utilized the isolated perfused rat lung model to produce lung injury by varying tidal volume and the level of positive end-expiratory pressure during mechanical ventilation. Pretreatment with KGF attenuated ventilator-induced lung injury (VILI). This was demonstrated by lower wet-to-dry lung weight ratios and less lung water accumulation in the KGF group. Further, KGF prevented the decline in dynamic compliance and alveolar protein accumulation in VILI. KGF pretreatment reduced alveolar accumulation of intravascularly administered fluorescein isothiocyanate-labeled high-molecular-weight dextran. Thus, pretreatment with KFG attenuates injury in this ex vivo model of VILI via mechanisms that prevent increases in permeability.
Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine produced principally by mononuclear cells, is released in response to a variety of pulmonary pathogens. We hypothesized that ...release of TNF in the lung is a normal part of the host response to intratracheal challenge with Pneumocystis carinii. To test this hypothesis, we measured TNF in bronchoalveolar lavage fluid (BALF) in normal and CD4-depleted mice at various intervals in acute and chronically infected animals. To assess the cell of origin and the control of TNF release in the lung, we measured mRNA for TNF by a competitive polymerase chain reaction and assessed the capacity of adherence-enriched cells to produce TNF in vitro in response to lipopolysaccharide. Our data demonstrate that TNF peaks at 3 h in both control and CD4-depleted mice after acute challenge with P. carinii and this increase in TNF precedes the influx of inflammatory cells into the lung. TNF levels in BALF return to undetectable levels by day 3. In chronically infected animals, there is a 5-fold increase in mRNA for TNF in adherent cells which is associated with an increased capacity to release TNF in vitro. These data suggest that TNF is a normal host response to P. carinii infection; however, there is no difference in acute TNF release between control animals that clear their infection and CD4-depleted animals that develop chronic infection. TNF is upregulated in chronically infected animals, but CD4 depletion results in the loss of additional host factors essential for resolution of this infection.
Pathophysiology of pneumonia Nelson, S; Mason, C M; Kolls, J ...
Clinics in chest medicine,
03/1995, Volume:
16, Issue:
1
Journal Article
Peer reviewed
The care and management of the pneumonia patient are formidable challenges to the physician. As long as the basic underlying host defense defects in these patients remain elusive, the clinician's ...approach will remain symptomatic and empirical. Further knowledge of the underlying pathophysiology of pneumonia will undoubtedly provide innovative approaches to both the prevention and the early and effective treatment of this infection. Clearly, the development of a multimodal approach, including components of immune modulation and immune restoration, is needed to improve the multiple defects in the host defense system; however, the normal host defense system operates in a delicate balance. Efforts to stimulate the immune system nonselectively may prove to be as deleterious to the patient as are the negative effects of their immunocompromised state.
The objectives of the present study were to: (1) evaluate the safety of Filgrastim therapy in non-neutropenic patients with severe community-acquired pneumonia; (2) determine the absolute neutrophil ...count (ANC) response to various dosages of Filgrastim in non-neutropenic patients with active infection; and (3) describe the impact of therapy with Filgrastim in combination with antibiotics on selected pneumonia-related clinical parameters.
The study design was an open-label, dose-ranging, clinical trial, set in the General Clinical Research Unit of a large, public community hospital. The study population consisted of 30 patients who had presented to the Emergency Department with severe, community-acquired pneumonia.
One of five dosages (75, 150, 300, 450 or 600 μg day
−1) of Filgrastim (r-metHuG-CSF) was given subcutaneously daily for 10 days, until discharge or until the absolute neutrophil count >75 × 10
9 1
−1, whichever was earlier. Vital signs, pulse oximetry, arterial blood gases, daily complete blood counts with differential, serum chemistries, coagulation profiles, electrocardiograms, chest radiographs, plasma G-CSF concentrations and duration of hospitalization were measured.
There was no evidence of Filgrastim-related lung injury or evidence of extra-pulmonary toxicity. There was no apparent dose-response effect of Filgrastim on pneumonia-related clinical variables. Dosages of Filgrastim between 150 and 600 μg day
−1 had similar effects on increasing the ANC.
Filgrastim appeared to be safe in non-neutropenic patients with severe, community-acquired pneumonia when given in dosages of 75–600 μg day
−1 in combination with appropriate antibiotic therapy. Further study is needed to determine the effect of Filgrastim on morbidity, mortality and duration of symptoms in this patient population.
Continuous geodetic measurements from convergent margins have shown that deep transient creep events can release large amounts of strain energy without detectable seismic shaking, and they are thus ...known as slow or silent earthquakes. Because subduction zones generate the largest earthquakes, seismic hazard assessment relies on understanding the degree to which slow earthquakes reduce the energy released by infrequent large earthquakes. We present data that indicate the periodicity of slow earthquakes in Cascadia and the current onset of such an event.
Continuous-infusion prostacyclin improves symptom scores and decreases mortality in patients with primary pulmonary hypertension, but use of prostacyclin in patients with pulmonary veno-occlusive ...disease may precipitate pulmonary edema. A patient with pulmonary veno-occlusive disease received a graduated intravenous infusion of prostacyclin and pulmonary capillary pressures were calculated during prostacyclin dose ranging. Calculated capillary pressure increased with low-dose prostacyclin (≤6 ng/kg/min) but decreased with higher doses. These data suggest that the post-capillary pulmonary venules in our patient had reversible vasomotor tone, but required a higher dose of prostacyclin to vasodilate than did the pre-capillary arterioles.
We hypothesized that therapy with granulocyte-macrophage colony stimulating factor (GM-CSF) would decrease intensity of murine Pneumocystis carinii pneumonia by upregulating alveolar macrophage ...function. Mice were depleted of CD4+ T lymphocytes and then inoculated intratracheally with P. carinii. Four weeks later, they received recombinant murine GM-CSF (rmGM-CSF) 5 micrograms/d subcutaneously for 7 and 14 d. At the end of therapy lung tissue was scored for intensity of P. carinii infection by silver methenamine stain and for inflammation by hematoxylin-eosin stain. We found that rmGM-CSF therapy significant decreased the intensity scores of PCP infection in comparison to control mice (1.88 +/- 0.47 vs 3.06 +/- 0.12, p < 0.001). Inflammation scores were not significantly different in the rmGM-CSF group compared with the control group (1.83 +/- 0.47 vs 2.83 +/- 0.67). Alveolar macrophages from mice treated with rmGM-CSF released significantly more tumor necrosis factor-alpha (TNF-alpha) than cells from control mice after in vitro stimulation with lipopolysaccharide (LPS) alone (2.65 +/- 0.30 vs 1.45 +/- 0.26 ng/ml, p = 0.01) or with LPS plus murine recombinant interferon-gamma (4.16 +/- 0.51 vs 2.25 +/- 0.34 ng/ml, p = 0.01). We conclude that GM-CSF therapy reduces the intensity of PCP and this effect is associated with an enhanced alveolar macrophage TNF-alpha production.
Ethanol suppresses functions of the polymorphonuclear leukocyte (PMNL), seriously compromising normal host defenses against pneumonia. Because granulocyte colony-stimulating factor (G-CSF) augments ...the number and function ofPMNL, the effect ofG-CSF on the antibacterial defenses of the lung in normal and acutely intoxicated rats was studied. Animals received G-CSF or vehicle twice a day for 2 days, then ethanol or saline, followed by challenge with Klebsiella pneumoniae. K. pneumoniae elicited an intrapulmonary influx of PMNL in control rats that was markedly suppressed by prior ethanol administration. G-CSF augmented the recruitment of PMNL into the lungs of control rats and significantly attenuated the adverse effects of ethanol on PMNL entry into the lung. G-CSF enhanced intrapulmonary bactericidal activity against this pathogen in normal and ethanol-treated rats. All intoxicated rats pretreated with the vehicle died, while >90% of rats pretreated with G-CSF survived. These findings suggest a potential role for G-CSF in mitigating the adverse effects of ethanol on PMNL delivery and pulmonary host defenses.
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