Secretory leukoprotease inhibitor attenuates lung injury induced by continuous air embolization into sheep

1995 ◽  
Vol 79 (4) ◽  
pp. 1163-1172 ◽  
Author(s):  
J. R. Gossage ◽  
E. A. Perkett ◽  
J. M. Davidson ◽  
B. C. Starcher ◽  
D. Carmichael ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neutrophil Elastase ◽  
Serine Proteases ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor ◽  
Arterial Circulation ◽  
Chronic Pulmonary Hypertension ◽  
Lung Lymph

Continuous air embolization (CAE) into the pulmonary arterial circulation of sheep results in functional and structural changes of chronic pulmonary hypertension. Release of elastin peptides into lung lymph during CAE and attenuation of CAE-induced pulmonary hypertension by neutrophil depletion suggest that neutrophil elastase may contribute to these changes. To investigate this notion, we treated awake sheep with a potent neutrophil elastase inhibitor, recombinant secretory leukoprotease inhibitor (SLPI) (100 mg/day by aerosol), during 12 days of CAE (CAE+SLPI; n = 7). Controls included sheep receiving CAE + vehicle (VEH) (n = 6), VEH alone (n = 3), and SLPI alone (n = 3). SLPI significantly attenuated the CAE-induced increases in lung lymph flow (day 8; 2.3 +/- 0.5 vs. 5.6 +/- 1.7 ml/15 min), protein clearance (day 8; 1.36 +/- 0.32 vs. 3.08 +/- 0.84 ml/15 min), and elastin peptide concentration (day 8; 243 +/- 41 vs. 398 +/- 44 ng/ml). SLPI delayed the onset of sustained pulmonary hypertension from day 8 to day 12. Both CAE groups showed similar structural changes in the pulmonary arteries. SLPI was well tolerated in control sheep and did not affect hemodynamics or structure. We conclude that serine proteases may contribute to the early initiation of chronic pulmonary hypertension but do not play a striking role in its eventual development.

Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension

2007 ◽  
Vol 293 (1) ◽  
pp. L1-L8 ◽  
Author(s):  
Enrique Arciniegas ◽  
Maria G. Frid ◽  
Ivor S. Douglas ◽  
Kurt R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Serine Proteases ◽  
Structural Changes ◽  
Transforming Growth Factor ◽  
Pulmonary Arteries ◽  
Potential Contribution ◽  
Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

All forms of pulmonary hypertension are characterized by structural changes in pulmonary arteries. Increased numbers of cells expressing α-smooth muscle (α-SM) actin is a nearly universal finding in the remodeled artery. Traditionally, it was assumed that resident smooth muscle cells were the exclusive source of these newly appearing α-SM actin-expressing cells. However, rapidly emerging experimental evidence suggests other, alternative cellular sources of these cells. One possibility is that endothelial cells can transition into mesenchymal cells expressing α-SM actin and that this process contributes to the accumulation of SM-like cells in vascular pathologies. We review the evidence that endothelial-mesenchymal transition is an important contributor to cardiac and vascular development as well as to pathophysiological vascular remodeling. Recent work has provided evidence for the role of transforming growth factor-β, Wnt, and Notch signaling in this process. The potential roles of matrix metalloproteinases and serine proteases are also discussed. Importantly, endothelial-mesenchymal transition may be reversible. Thus insights into the mechanisms controlling endothelial-mesenchymal transition are relevant to vascular remodeling and are important as we consider new therapies aimed at reversing pulmonary vascular remodeling.

Structure Function Correlates in the Pulmonary Vasculature during Acute Lung Injury and Chronic Pulmonary Hypertension

1991 ◽  
Vol 19 (4_part_1) ◽  
pp. 447-457 ◽  
Author(s):  
Barbara Meyrick
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Edema ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Capillary Endothelium ◽  
Functional Changes ◽  
Structural Types ◽  
Chronic Pulmonary Hypertension ◽  
Hemodynamic Measurements

Arteries, veins, and capillaries comprise the pulmonary vasculature. Three structural types of artery and vein are identified, the most muscular vessels being the largest. For example, arteries that accompany the preacinar arteries are muscular in structure while those within the acinus may be either, muscular, partially muscular or non-muscular. These small intraacinar arteries contribute much to the hemodynamic behavior of the lung. Pulmonary edema results from damage to the capillary endothelium while chronic pulmonary hypertension is characterized by structural alterations in the pulmonary arteries. Correlation of the structural and functional changes of chronic pulmonary hypertension suggest that the increases in medial and adventitial thickness of the muscular preacinar arteries are secondary to the onset of this disease, while the changes in the peripheral arteries—appearance of muscle in smaller intraacinar arteries than normal and reduction in arterial volume—contribute to the rise in pulmonary artery pressure and pulmonary vascular resistance. Such correlations of structure and hemodynamic measurements demand that the lung be fixed in a simple and standardized manner. Available methodology to evaluate the structural changes that occur during the development of pulmonary edema and chronic pulmonary hypertension are described.

Pulmonary hypertension and increased vasoreactivity caused by repeated indomethacin in sheep

1985 ◽  
Vol 59 (2) ◽  
pp. 443-452 ◽  
Author(s):  
B. Meyrick ◽  
M. E. Niedermeyer ◽  
M. L. Ogletree ◽  
K. L. Brigham
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Blood Gases ◽  
Repeated Administration ◽  
Base Line ◽  
External Diameter ◽  
Arterial Circulation ◽  
Peripheral Lung ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial

Six chronically catheterized awake sheep were given the cyclooxygenase inhibitor indomethacin (5 mg/kg) twice a day over a 3-wk period. Three sheep receiving vehicle alone served as controls. Pulmonary arterial, left atrial, and systemic arterial pressures, cardiac output, blood gases, and pH were measured biweekly. Pulmonary vasoreactivity to 12% O2 and an analogue of prostaglandin H2 (PGH2-A) was also assessed. As a percent of base line, indomethacin caused a doubling in pulmonary vascular resistance (3 wk = 190 +/- 26%, mean +/- SE) and a 50% increase in pulmonary arterial pressure (3 wk = 151 +/- 9%). Vasoreactivity to 12% O2 increased approximately fourfold during the 1st wk of treatment and then declined. Vasoreactivity to PGH2-A increased steadily, nearly doubling by 3 wk. Light-microscopic counts of peripheral lung biopsy tissue revealed marked sequestration of granulocytes. Morphometric techniques applied to lungs removed at autopsy and fixed with the pulmonary arteries distended with barium gelatin mixture showed a significant reduction in number of barium-filled peripheral arteries and reduction in their external diameter. We conclude that repeated administration of indomethacin alters pulmonary vasoreactivity and causes sustained pulmonary hypertension. Structural studies reveal peripheral lung inflammation and changes in the arterial circulation that are perhaps more consistent with maintained vasoconstriction than chronic pulmonary hypertension.

Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706

1999 ◽  
Vol 66 (5) ◽  
pp. 501-508 ◽  
Author(s):  
F KOIZUMI ◽  
M MURAKAMI ◽  
H KAGEYAMA ◽  
M KATASHIMA ◽  
M TERAKAWA ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor

Study on Perioperative Administration of a Neutrophil Elastase Inhibitor for Interstitial Pneumonias

2017 ◽  
Vol 103 (6) ◽  
pp. 1781-1787 ◽  
Author(s):  
Mariko Fukui ◽  
Kazuya Takamochi ◽  
Shiaki Oh ◽  
Takeshi Matsunaga ◽  
Kazuhiro Suzuki ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor

scholarly journals Neutrophil elastase inhibitor sivelestat ameliorates gefitinib-naphthalene-induced acute pneumonitis in mice

2017 ◽  
Author(s):  
Hironori Mikumo ◽  
Toyoshi Yanagihara ◽  
Naoki Hamada ◽  
Eiji Harada ◽  
Saiko Ogata-Suetsugu ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Therapeutic Agent ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Lavage Fluid ◽  
Egfr Mutations ◽  
Airway Epithelial ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor ◽  
Promising Therapeutic Agent

ABSTRACTBackground and objectiveGefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is an effective therapeutic agent for non-small cell lung cancer with EGFR mutations. It can cause severe acute pneumonitis in some patients. We previously demonstrated that mice with naphthalene-induced airway epithelial injury developed severe gefitinib-induced pneumonitis and that neutrophils played important roles in the development of the disease. This study aimed to investigate the effects of the neutrophil elastase inhibitor sivelestat on gefitinib-induced pneumonitis in mice.MethodsC57BL/6J mice received naphthalene (200 mg/kg) intraperitoneally on day 0. Gefitinib (250 or 300 mg/kg) was orally administered to mice from day −1 until day 13. Sivelestat (150 mg/kg) was administered intraperitoneally from day 1 until day 13. Bronchoalveolar lavage fluid (BALF) and lung tissues were sampled on day 14.ResultsSivelestat treatment significantly reduced the protein level, neutrophil count, neutrophil elastase activity in BALF, and severity of histopathologic findings on day 14 for mice administered with 250 mg/kg of gefitinib. Moreover, sivelestat treatment significantly improved the survival of mice administered with 300 mg/kg of gefitinib. Conclusions: These results indicate that sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.Summary statementNeutrophil elastase inhibitor sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.

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