scholarly journals Impaired alveolar liquid clearance after 48-h isoproterenol infusion spontaneously recovers by 96 h of continuous infusion

2006 ◽  
Vol 291 (2) ◽  
pp. L252-L256 ◽  
Author(s):  
Michael B. Maron ◽  
Hans G. Folkesson ◽  
Sonya M. Stader ◽  
Cheryl M. Hodnichak
Keyword(s):  
Continuous Infusion ◽  
Time Course ◽  
Lung Epithelium ◽  
Osmotic Minipump ◽  
Peripheral Lung ◽  
Distal Lung ◽  
Time Periods ◽  
Isoproterenol Infusion ◽  
Alveolar Liquid Clearance ◽  
Alveolar Liquid

We previously demonstrated that 48-h isoproterenol (Iso) infusion in rats impaired the ability of β-adrenoceptor (β-AR) agonists to increase alveolar liquid clearance (ALC). In this study, we determined whether this impairment persisted over longer time periods by infusing 400 μg·kg−1·h−1 Iso by osmotic minipump for 24–144 h ( n = 6–7/group). ALC in control rats was 19.0 ± 2.4 (SD)% of instilled volume absorbed per hour. In Iso-infused rats, ALC was elevated at 24 h (34.9 ± 2.4%) and decreased at 48 h (15.2 ± 4.4%) and had recovered to 24 h values at 96 h (37.3 ± 3.8%) and 144 h (35.2 ± 3.3%). Plasma Iso concentrations remained elevated at all Iso infusion times. Peripheral lung β2-AR expression exhibited a parallel time course, with a reduction in expression observed at 48 h, followed by an increase to 24 h values at 96 and 144 h. Propranolol prevented the increase in ALC observed at 96 and 144 h, indicating that the recovery in ALC was mediated by a recovery of β-AR function and β-AR signaling. ALC at 96 and 144 h could not be further increased by terbutaline, indicating that ALC was maximally stimulated. These data indicate that recovery of β-AR-stimulated ALC can occur in the continued presence of Iso and is mediated by a recovery of the ability of the distal lung epithelium to respond to β-AR stimulation.

PKA delivery to the distal lung air spaces increases alveolar liquid clearance after isoproterenol-induced alveolar epithelial PKA desensitization

2005 ◽  
Vol 289 (2) ◽  
pp. L349-L354 ◽  
Author(s):  
Michael B. Maron ◽  
Hans G. Folkesson ◽  
Sonya M. Stader ◽  
Jon M. Walro
Keyword(s):  
Protein Delivery ◽  
Immunohistochemical Localization ◽  
Biologically Active ◽  
Lung Epithelium ◽  
Alveolar Epithelial ◽  
Distal Airway ◽  
Distal Lung ◽  
Rate Limiting ◽  
Alveolar Liquid Clearance ◽  
Alveolar Liquid

Isoproterenol (Iso) infusion for 48 h in rats decreases the ability of β-adrenoceptor (β-AR) agonists to increase alveolar liquid clearance (ALC). An impairment in protein kinase A (PKA) function appears to be critical in producing the desensitized ALC response. To test this hypothesis, we used a novel protein delivery reagent (Chariot, Active Motif) to deliver either the PKA catalytic subunit or the PKA holoenzyme to the distal lung epithelium of Iso-infused rats (400 μg·kg−1·h−1, 48 h). After this infusion, ALC was measured by mass balance over 2 h. ALC in Iso-infused rats was 27.9% (SD 5.8) of instilled volume absorbed. Delivery of the catalytic PKA subunit to Iso-infused rats increased ALC to 47.7% (SD 8.9) ( P < 0.05). ALC in Iso-infused rats delivered the inactive PKA holoenzyme [29.6% (SD 2.5)] was not increased above baseline values. Subsequent holoenzyme activation by intravenous infusion of the stable cAMP analog Sp-8-Bromo-cAMPS increased ALC to 41.7% (SD 8.8) ( P < 0.05). Immunohistochemical localization of Chariot-delivered PKA revealed staining in the alveolar and distal airway epithelium. These data indicate that protein delivery reagents can be used to rapidly deliver biologically active proteins to the distal lung epithelium and that PKA desensitization may be an important rate-limiting event in the development of Iso-induced desensitization of the alveolar epithelial β-AR signaling pathway.

Prolonged isoproterenol infusion impairs the ability of β2-agonists to increase alveolar liquid clearance

2002 ◽  
Vol 282 (4) ◽  
pp. L666-L674 ◽  
Author(s):  
Eric E. Morgan ◽  
Cheryl M. Hodnichak ◽  
Sonya M. Stader ◽  
Kay C. Maender ◽  
John W. Boja ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Prolonged Exposure ◽  
Adrenergic Agonist ◽  
Ringer Lactate ◽  
Alveolar Epithelial ◽  
Atii Cell ◽  
Isoproterenol Infusion ◽  
Β2 Agonists ◽  
Alveolar Liquid Clearance ◽  
Alveolar Liquid

We determined if prolonged isoproterenol (Iso) infusion in rats impaired the ability of the β2-adrenergic agonist terbutaline to increase alveolar liquid clearance (ALC). We infused rats with Iso (at rates of 4, 40, or 400 μg · kg−1 · h−1) or vehicle (0.001 N HCl) for 48 h using subcutaneously implanted miniosmotic pumps. After this time, the rats were anesthetized, and ALC was determined (by mass-balance after instillation of Ringer lactate containing albumin into the lungs) under baseline conditions and after terbutaline administration. Baseline and terbutaline-stimulated ALC in vehicle-infused rats averaged, respectively, 19.6 ± 1.2% (SE) and 44.7 ± 1.5%/h. The ability of terbutaline to increase ALC was eliminated at 400 μg · kg−1 · h−1 Iso, inhibited by 26% at 40 μg · kg−1 · h−1 Iso, and was not affected by 4 μg · kg−1 · h−1 Iso. β-adrenergic receptor (βAR) density of freshly isolated alveolar epithelial type II (ATII) cells from Iso-infused rats was reduced by the 40 and 400 μg · kg−1 · h−1 infusion rates. These data demonstrate that prolonged exposure to β-agonists can impair the ability of β2-agonists to stimulate ALC and produce ATII cell βAR downregulation.

Effect of Covalent Serpin–Heparinoid Complexes on Plasma Thrombin Generation on Fetal Distal Lung Epithelium

2003 ◽  
Vol 28 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Leslie R. Berry ◽  
Petr Klement ◽  
Maureen Andrew ◽  
Anthony K. C. Chan
Keyword(s):  
Thrombin Generation ◽  
Lung Epithelium ◽  
Distal Lung

Dose-response relationship between plasma epinephrine concentration and alveolar liquid clearance in dogs

1998 ◽  
Vol 85 (5) ◽  
pp. 1702-1707 ◽  
Author(s):  
Michael B. Maron
Keyword(s):  
Dose Response ◽  
Respir Crit ◽  
Plasma Concentrations ◽  
Neurogenic Pulmonary Edema ◽  
Response Relationship ◽  
Plasma Epinephrine ◽  
Dose Response Relationship ◽  
Alveolar Liquid Clearance ◽  
Epinephrine Concentration ◽  
Alveolar Liquid

Previously, alveolar liquid clearance (ALC) was observed to increase in a canine model of neurogenic pulmonary edema (NPE) by adrenal epinephrine (S. M. Lane, K. C. Maender, N. E. Awender, and M. B. Maron. Am. J. Respir. Crit. Care Med. 158: 760–768, 1998). In this study the dose-response relationship between plasma epinephrine concentration and ALC was determined in anesthetized dogs by infusing epinephrine to produce plasma concentrations of 256 ± 37, 1,387 ± 51, 15,737 ± 2,161, and 363,997 ± 66,984 (SE) pg/ml ( n = 6 for each concentration) for 4 h and measuring the resultant ALC. The latter was determined by mass balance after instillation of autologous plasma into a lower lung lobe. These plasma concentrations produced ALCs of 14.3 ± 1.2, 20.5 ± 1.9, 30.1 ± 1.5, and 37.9 ± 2.7% of the instilled volume, respectively. ALC after the lowest infusion rate was not different from that previously observed under baseline conditions (14.1 ± 2.1%), whereas in a previous study of NPE, plasma epinephrine concentration increased to 7,683 ± 687 pg/ml and ALC was 30.4 ± 1.6%. These data indicate that, during recovery from canine NPE, ALC is not maximally stimulated and suggest that it might be possible to pharmacologically produce further increases in the rate of resolution of this form of edema.

scholarly journals Genomic Surveillance and Phylodynamic Analyses Reveal the Emergence of Novel Mutations and Co-mutation Patterns Within SARS-CoV-2 Variants Prevalent in India

2021 ◽  
Vol 12 ◽  
Author(s):  
Nupur Biswas ◽  
Priyanka Mallick ◽  
Sujay Krishna Maity ◽  
Debaleena Bhowmik ◽  
Arpita Ghosh Mitra ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Time Course ◽  
West Bengal ◽  
Genomic Diversity ◽  
Viral Population ◽  
Whole Genome ◽  
Novel Mutations ◽  
Frequent Mutations ◽  
Time Periods

Identification of the genomic diversity and the phylodynamic profiles of prevalent variants is critical to understand the evolution and spread of SARS-CoV-2 variants. We performed whole-genome sequencing of 54 SARS-CoV-2 variants collected from COVID-19 patients in Kolkata, West Bengal during August–October 2020. Phylogeographic and phylodynamic analyses were performed using these 54 and other sequences from India and abroad that are available in the GISAID database. We estimated the clade dynamics of the Indian variants and compared the clade-specific mutations and the co-mutation patterns across states and union territories of India over the time course. Frequent mutations and co-mutations observed within the major clades across time periods do not show much overlap, indicating the emergence of newer mutations in the viral population prevailing in the country. Furthermore, we explored the possible association of specific mutations and co-mutations with the infection outcomes manifested in Indian patients.

GATA6 regulates differentiation of distal lung epithelium

Development ◽  
2002 ◽  
Vol 129 (9) ◽  
pp. 2233-2246 ◽  
Author(s):  
Honghua Yang ◽  
Min Min Lu ◽  
Lili Zhang ◽  
Jeffrey A. Whitsett ◽  
Edward E. Morrisey
Keyword(s):  
Gene Expression ◽  
Epithelial Cell ◽  
Surfactant Protein ◽  
Gata Factor ◽  
Lung Epithelium ◽  
Alveolar Epithelial ◽  
Distal Lung ◽  
Transgenic Embryos

GATA6 is a member of the GATA family of zinc-finger transcriptional regulators and is the only known GATA factor expressed in the distal epithelium of the lung during development. To define the role that GATA6 plays during lung epithelial cell development, we expressed a GATA6-Engrailed dominant-negative fusion protein in the distal lung epithelium of transgenic mice. Transgenic embryos lacked detectable alveolar epithelial type 1 cells in the distal airway epithelium. These embryos also exhibited increased Foxp2 gene expression, suggesting a disruption in late alveolar epithelial differentiation. Alveolar epithelial type 2 cells, which are progenitors of alveolar epithelial type 1 cells, were correctly specified as shown by normal thyroid transcription factor 1 and surfactant protein A gene expression. However, attenuated endogenous surfactant protein C expression indicated that alveolar epithelial type 2 cell differentiation was perturbed in transgenic embryos. The number of proximal airway tubules is also reduced in these embryos, suggesting a role for GATA6 in regulating distal-proximal airway development. Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter. Together, these data implicate GATA6 as an important regulator of distal epithelial cell differentiation and proximal airway development in the mouse.

β-Adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats

2000 ◽  
Vol 89 (4) ◽  
pp. 1255-1265 ◽  
Author(s):  
James A. Frank ◽  
Yibing Wang ◽  
Oscar Osorio ◽  
Michael A. Matthay
Keyword(s):  
Pulmonary Edema ◽  
Left Atrial ◽  
Experimental Studies ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Adrenergic Agonist ◽  
Agonist Therapy ◽  
Arterial Blood ◽  
Alveolar Liquid Clearance ◽  
Alveolar Liquid

To determine whether β-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH2O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized β-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. β-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h ( P< 0.001). Because the rate of alveolar fluid clearance in rats is closer to human rates, we studied β-agonist therapy in rats, with hydrostatic pulmonary edema induced by volume overload (40% body wt infusion of Ringer lactate). β-Agonist therapy resulted in a significant decrease in excess lung water ( P < 0.01) and significant improvement in arterial blood gases by 2 h ( P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether β-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

Transforming growth factor-alpha increases alveolar liquid clearance in anesthetized ventilated rats

1996 ◽  
Vol 271 (2) ◽  
pp. L236-L244 ◽  
Author(s):  
H. G. Folkesson ◽  
J. F. Pittet ◽  
G. Nitenberg ◽  
M. A. Matthay
Keyword(s):  
Transforming Growth Factor ◽  
Adrenergic Agonist ◽  
Beta Adrenergic ◽  
Alveolar Epithelial ◽  
Factor Alpha ◽  
Beta Adrenergic Agonist ◽  
Camp Levels ◽  
Na Uptake ◽  
Alveolar Liquid Clearance ◽  
Alveolar Liquid

The effect of transforming growth factor-alpha (TGF-alpha) on alveolar liquid clearance was examined in ventilated, anesthetized rats. An isosmolar Ringer lactate solution with 10, 50, or 200 ng/ml TGF-alpha and 125I-labeled albumin as the alveolar protein tracer was instilled into the right lower lung lobe; the rats were studied for 1 and 4 h. Compared with control rats, addition of 50 ng/ml TGF-alpha to the instilled fluid increased alveolar liquid clearance by 47% over 1 h and by 66% over 4 h (P < 0.05). This increase was similar to the 50% increase in alveolar liquid clearance over 1 h in rats instilled with a beta-adrenergic agonist, salmeterol (28). There was a dose-dependent effect of TGF-alpha (10, 50, 200 ng/ml) on alveolar liquid clearance. The combination of both TGF-alpha and salmeterol did not have an additive effect on alveolar liquid clearance. The TGF-alpha-stimulated increase in alveolar liquid clearance was inhibited by amiloride (10(-4) M), indicating that the increase in clearance depended on increased Na+ uptake across the alveolar epithelium. There was only a twofold increase in intracellular cAMP levels in isolated rat alveolar epithelial type II cells after stimulation with TGF-alpha. In contrast, beta-adrenergic agonist treatment increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels more than tenfold. Genistein (10(-6) M), a tyrosine protein kinase inhibitor, inhibited the TGF-alpha-stimulated increase in alveolar liquid clearance. In summary, TGF-alpha can stimulate in vivo alveolar liquid clearance at a rate similar to beta-adrenergic stimulation by increasing Na+ uptake by alveolar epithelial type II cells. However, the effect may be mediated by a non-cAMP dependent mechanism. Because genistein blocked the increase in alveolar fluid clearance, the signal transduction may involve genistein-dependent phosphorylation.

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