scholarly journals Keratinocyte growth factor attenuates hydrostatic pulmonary edema in an isolated, perfused rat lung model

2001 ◽  
Vol 280 (3) ◽  
pp. H1311-H1317 ◽  
Author(s):  
David A. Welsh ◽  
Benoit P. H. Guery ◽  
Bennett P. Deboisblanc ◽  
Elizabeth P. Dobard ◽  
Colette Creusy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Edema ◽  
Ex Vivo ◽  
Keratinocyte Growth Factor ◽  
Lung Model ◽  
Rat Lung ◽  
Ex Vivo Model ◽  
Lung Weight ◽  
Edema Formation ◽  
Alveolar Epithelial

Hydrostatic pulmonary edema is a common complication of congestive heart failure, resulting in substantial morbidity and mortality. Keratinocyte growth factor (KGF) is a mitogen for type II alveolar epithelial and microvascular cells. We utilized the isolated perfused rat lung model to produce hydrostatic pulmonary edema by varying the left atrial and pulmonary capillary pressure. Pretreatment with KGF attenuated hydrostatic edema formation. This was demonstrated by lower wet-to-dry lung weight ratios, histological evidence of less alveolar edema formation, and reduced alveolar accumulation of intravascularly administered FITC-labeled large-molecular-weight dextran in rats pretreated with KGF. Thus KGF attenuates injury in this ex vivo model of hydrostatic pulmonary edema via mechanisms that prevent increases in alveolar-capillary permeability.

scholarly journals Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

2020 ◽  
Author(s):  
Saurabh Aggarwal ◽  
Ahmed Lazrak ◽  
Israr Ahmad ◽  
Zhihong Yu ◽  
Ayesha Bryant ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Ex Vivo ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Inhalation Injury ◽  
Alveolar Cells ◽  
Alveolar Epithelial ◽  
Single Intramuscular Injection ◽  
Free Heme ◽  
Gas Inhalation

ABSTRACTWe previously reported that cell-free heme (CFH) is increased in the plasma of patients with acute and chronic lung injury and causes pulmonary edema in animal model of acute respiratory distress syndrome (ARDS) post inhalation of halogen gas. However, the mechanisms by which CFH causes pulmonary edema are unclear. Herein we report for the first time the presence of CFH and chlorinated lipids (formed by the interaction of halogen gas, Cl2, with plasmalogens) in the plasma of patients and mice exposed to Cl2 gas. Ex vivo incubation of red blood cells (RBC) with halogenated lipids caused oxidative damage to RBC cytoskeletal protein spectrin, resulting in hemolysis and release of CFH. A single intramuscular injection of the heme-scavenging protein hemopexin (4 µg/kg body weight) in mice, one hour post halogen exposure, reversed RBC fragility and decreased CFH levels to those of air controls. Patch clamp and short circuit current measurements revealed that CFH inhibited the activity of amiloride-sensitive (ENaC) and cation sodium (Na+) channels in mouse alveolar cells and trans-epithelial Na+ transport across human airway cells with EC50 of 125 nM and 500 nM, respectively. Molecular modeling identified 22 putative heme-docking sites on ENaC (energy of binding range: 86-1563 kJ/mol) with at least 2 sites within its narrow transmembrane pore, potentially capable of blocking Na+ transport across the channel. In conclusion, results suggested that CFH mediated inhibition of ENaC activity may be responsible for pulmonary edema post inhalation injury.

Alpha-thrombin-induced pulmonary vasoconstriction

1987 ◽  
Vol 63 (5) ◽  
pp. 1993-2000 ◽  
Author(s):  
M. J. Horgan ◽  
J. W. Fenton ◽  
A. B. Malik
Keyword(s):  
Pulmonary Edema ◽  
Base Line ◽  
Thrombin Injection ◽  
Weight Changes ◽  
Lung Weight ◽  
Edema Formation ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Hemodynamic ◽  
Proteolytic Site ◽  
Synthase Inhibitor

We examined the direct effects of thrombin on pulmonary vasomotor tone in isolated guinea pig lungs perfused with Ringer albumin (0.5% g/100 ml). The injection of alpha-thrombin (the native enzyme) resulted in rapid dose-dependent increases in pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Ppc), which were associated with an increase in the lung effluent thromboxane B2 concentration. The Ppa and Ppc responses decreased with time but then increased again within 40 min after thrombin injection. The increases in Ppc were primarily the result of postcapillary vasoconstriction. Pulmonary edema as evidenced by marked increases (60% from base line) in lung weight occurred within 90 min after thrombin injection. Injection of modified thrombins (i.e., gamma-thrombin lacking the fibrinogen recognition site or i-Pr2P-alpha-thrombin lacking the serine proteolytic site) was not associated with pulmonary hemodynamic or weight changes nor did they block the effects of alpha-thrombin. Indomethacin (a cyclooxygenase inhibitor), dazoxiben (a thromboxane synthase inhibitor), or hirudin (a thrombin antagonist) inhibited the thrombin-induced pulmonary vasoconstriction, as well as the pulmonary edema. We conclude that thrombin-induced pulmonary vasoconstriction is primarily the result of constriction of postcapillary vessels, and the response is mediated by generation of cyclooxygenase-derived metabolites. The edema formation is also dependent on activation of the cyclooxygenase pathway. The proteolytic site of alpha-thrombin is required for the pulmonary vasoconstrictor and edemogenic responses.

Keratinocyte Growth Factor Modulates Alveolar Epithelial Cell PhenotypeIn Vitro: Expression of Aquaporin 5

1998 ◽  
Vol 18 (4) ◽  
pp. 554-561 ◽  
Author(s):  
Zea Borok ◽  
Richard L. Lubman ◽  
Spencer I. Danto ◽  
Xiao-Ling Zhang ◽  
Stephanie M. Zabski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Alveolar Epithelial Cell ◽  
Keratinocyte Growth Factor ◽  
Aquaporin 5 ◽  
Alveolar Epithelial

Apoptosis and DNA damage in type 2 alveolar epithelial cells cultured from hyperoxic rats

1998 ◽  
Vol 274 (5) ◽  
pp. L714-L720 ◽  
Author(s):  
Sue Buckley ◽  
Lora Barsky ◽  
Barbara Driscoll ◽  
Kenneth Weinberg ◽  
Kathryn D. Anderson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Cellular Response ◽  
Ex Vivo ◽  
Keratinocyte Growth Factor ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Dna Laddering

Apoptosis is a genetically controlled cellular response to developmental stimuli and environmental insult that culminates in cell death. Sublethal hyperoxic injury in rodents is characterized by a complex but reproducible pattern of lung injury and repair during which the alveolar surface is damaged, denuded, and finally repopulated by type 2 alveolar epithelial cells (AEC2). Postulating that apoptosis might occur in AEC2 after hyperoxic injury, we looked for the hallmarks of apoptosis in AEC2 from hyperoxic rats. A pattern of increased DNA end labeling, DNA laddering, and induction of p53, p21, and Bax proteins, strongly suggestive of apoptosis, was seen in AEC2 cultured from hyperoxic rats when compared with control AEC2. In contrast, significant apoptosis was not detected in freshly isolated AEC2 from oxygen-treated rats. Thus the basal culture conditions appeared to be insufficient to ensure the ex vivo survival of AEC2 damaged in vivo. The oxygen-induced DNA strand breaks were blocked by the addition of 20 ng/ml of keratinocyte growth factor (KGF) to the culture medium from the time of plating and were partly inhibited by Matrigel or a soluble extract of Matrigel. KGF treatment resulted in a partial reduction in the expression of the p21, p53, and Bax proteins but had no effect on DNA laddering. We conclude that sublethal doses of oxygen in vivo cause damage to AEC2, resulting in apoptosis in ex vivo culture, and that KGF can reduce the oxygen-induced DNA damage. We speculate that KGF plays a role as a survival factor in AEC2 by limiting apoptosis in the lung after acute hyperoxic injury.

Alterations of filtration coefficients in pulmonary edema of different pathogenesis

1992 ◽  
Vol 73 (6) ◽  
pp. 2396-2402 ◽  
Author(s):  
T. Koch ◽  
H. P. Duncker ◽  
S. Rosenkranz ◽  
H. Neuhof ◽  
K. Van Ackern
Keyword(s):  
Arachidonic Acid ◽  
Pulmonary Edema ◽  
Barrier Function ◽  
Diclofenac Sodium ◽  
Venous Pressure ◽  
Lung Weight ◽  
Edema Formation ◽  
Capillary Filtration ◽  
Control Value ◽  
Isolated Cell

Different pathomechanisms in the development of pulmonary edema are being discussed. We investigated the effect of pathogenetically varying forms of edema on lung vascular barrier function in isolated cell-free perfused rabbit lungs. As an index of permeability, capillary filtration coefficients (Kfc) were determined from the slope of lung weight change over periods of stepwise venous pressure elevation (5, 7.5, and 10 mmHg) before (controls) and 60 min after edema induction. Edema was induced by venous congestion (n = 6), by application of arachidonic acid in the presence of diclofenac sodium (n = 6), and by elastase application (n = 6). Control values ranged from 0.28 to 0.51 ml.min-1 x mmHg-1 x 100 g-1. Kfc was significantly enhanced after edema induction up to 243% of control value in the hydrostatic edema, 357% in the arachidonic acid edema, and 594% in the elastase edema. When the alterations in capillary filtration due to the different types of edema were compared, Kfc was significantly higher in the proteinase edema, indicating an irreversibly damaged barrier function. These data exemplify different pathophysiological characteristics due to the pathogenesis of interstitial edema formation.

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