scholarly journals Pulmonary responses to acute ozone exposure in fasted mice: effect of leptin administration

2007 ◽  
Vol 102 (1) ◽  
pp. 149-156 ◽  
Author(s):  
Richard A. Johnston ◽  
Todd A. Theman ◽  
Raya D. Terry ◽  
Erin S. Williams ◽  
Stephanie A. Shore
Keyword(s):  
Bronchoalveolar Lavage ◽  
Continuous Infusion ◽  
Pulmonary Inflammation ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Pulmonary Mechanics ◽  
Serum Leptin ◽  
Mechanistic Basis ◽  
Inflammatory Profile ◽  
Induced Changes

Leptin is a satiety hormone that also has proinflammatory effects, including augmentation of ozone-induced pulmonary inflammation. The purpose of this study was to determine whether reductions in endogenous levels of leptin can attenuate pulmonary responses to ozone. To reduce serum leptin, we fasted mice overnight before ozone exposure. Fasting caused a marked reduction in serum leptin to approximately one-sixth the levels observed in fed mice, and continuous infusion of leptin via Alzet micro-osmotic pumps restored serum leptin to, but not above, fed levels. Ozone exposure (2 ppm for 3 h) caused a significant, ∼40% increase in pulmonary resistance ( P < 0.01) and increased airway responsiveness in fasted but not in fed mice. The increased effect of ozone on pulmonary mechanics and airway responsiveness in fasted mice was not observed when leptin was restored via continuous infusion. Ozone exposure caused pulmonary inflammation, as evident by increases in bronchoalveolar lavage cells, protein, and soluble tumor necrosis factor receptors. There was no effect of fasting status on ozone-induced changes in the bronchoalveolar lavage inflammatory profile, and leptin treatment did not alter these responses. Our results indicate that fasting augments ozone-induced changes in pulmonary mechanics and airway responsiveness in mice. These effects of fasting are the result of declines in serum leptin. The mechanistic basis for this protective effect of leptin in fasted mice remains to be determined but is not related to effects on ozone-induced inflammation.

C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

2004 ◽  
Vol 287 (6) ◽  
pp. L1172-L1177 ◽  
Author(s):  
Shinsuke Murakami ◽  
Noritoshi Nagaya ◽  
Takefumi Itoh ◽  
Takafumi Fujii ◽  
Takashi Iwase ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Continuous Infusion ◽  
Natriuretic Peptide ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Physiological Role ◽  
Immunohistochemical Analysis ◽  
Lavage Fluid ◽  
Ki 67

C-type natriuretic peptide (CNP) has been shown to play an important role in the regulation of vascular tone and remodeling. However, the physiological role of CNP in the lung remains unknown. Accordingly, we investigated whether CNP infusion attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. After intratracheal injection of BLM or saline, mice were randomized to receive continuous infusion of CNP or vehicle for 14 days. CNP infusion significantly reduced the total number of cells and the numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Interestingly, CNP markedly reduced bronchoalveolar lavage fluid IL-1β levels. Immunohistochemical analysis demonstrated that CNP significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. CNP infusion significantly attenuated BLM-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. CNP markedly decreased the number of Ki-67-positive cells in fibrotic lesions of the lung, suggesting antiproliferative effects of CNP on pulmonary fibrosis. Kaplan-Meier survival curves demonstrated that BLM mice treated with CNP had a significantly higher survival rate than those given vehicle. These results suggest that continuous infusion of CNP attenuates BLM-induced pulmonary fibrosis and improves survival in BLM mice, at least in part by inhibition of pulmonary inflammation and cell proliferation.

Hypercapnic ventilatory responses in mice differentially susceptible to acute ozone exposure

1993 ◽  
Vol 75 (6) ◽  
pp. 2613-2619 ◽  
Author(s):  
C. G. Tankersley ◽  
R. S. Fitzgerald ◽  
W. A. Mitzner ◽  
S. R. Kleeberger
Keyword(s):  
Minute Ventilation ◽  
Pulmonary Inflammation ◽  
Inbred Strains ◽  
Ozone Exposure ◽  
Whole Body ◽  
Ventilatory Control ◽  
Air Exposure ◽  
Ventilatory Responses ◽  
Inbred Strains Of Mice ◽  
Induced Changes

Susceptibility to ozone (O3)-induced pulmonary inflammation is greater in C57BL/6J (B6) than in C3H/HeJ (C3) strain of mice. We tested the hypothesis that altered ventilatory control occurs in B6 mice to a greater extent than in C3 mice after acute O3 exposure. Age-, sex-, and weight-matched C3 and B6 mice were exposed for 3 h to either 2 ppm O3 or filtered air. One and 24 h after O3 or air exposure, whole body plethysmography was used to measure breathing frequency (f), tidal volume (VT), and minute ventilation (VE). To assess changes in ventilatory control, mice were challenged by the elevation of fractional concentration of inspired CO2 levels to 5 and 8% in air for 10 min. After air exposure, there were significantly (P < 0.01) greater changes in VE in B6 than in C3 mice. Hypercapnia-induced changes in VE were significantly (P < 0.01) attenuated in B6 mice 1 h after O3 exposure. VT was significantly (P < 0.01) reduced 1 h after O3 in B6 and C3 mice; however, C3 mice increased f to sustain the hypercapnic VE response similar to air exposure. In contrast, the diminished VT in B6 mice 1 h after O3 occurred coincident with significantly (P < 0.01) reduced f, mean inspiratory flow, and slope of VE-to-%CO2 relationship compared with air exposure. Altered hypercapnic VE in B6 mice was partially reversed 24 h after O3 relative to air-exposed levels. These data suggest that control of ventilation during phenotypic response to CO2 is governed, in part, by genetic factors in inbred strains of mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Indomethacin and FPL-57231 inhibit antigen-induced airway hyperresponsiveness in sheep

1986 ◽  
Vol 61 (3) ◽  
pp. 864-872 ◽  
Author(s):  
S. Lanes ◽  
J. S. Stevenson ◽  
E. Codias ◽  
A. Hernandez ◽  
M. W. Sielczak ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Airway Responsiveness ◽  
Late Response ◽  
Early Release ◽  
Acute Response ◽  
Lung Resistance ◽  
Leukotriene Antagonist ◽  
Airway Responses

We compared the development of antigen-induced airway hyperresponsiveness (AHR) 24 h after challenge with Ascaris suum antigen in allergic sheep with acute (n = 7) and with dual (n = 7) airway responses and then attempted to modify this AHR. Cholinergic airway responsiveness was determined by measuring the carbachol dose required to increase specific lung resistance (sRL) 150% (i.e., PC150). Subsequently the sheep were challenged with antigen and sRL was measured at predetermined times to document the presence or absence of a late response. PC150 was redetermined 24 h later followed by bronchoalveolar lavage (BAL) to assess inflammation. Only dual responders developed AHR (PC150 decreased, P less than 0.05). There were no significant differences in BAL between the two groups. Six dual responders were then, on separate occasions (greater than or equal to 3 wk), pretreated with placebo, indomethacin (2 mg/kg iv), or a leukotriene antagonist, FPL-57231 (30 mg inhaled). Neither agent significantly affected the acute response to antigen. Only FPL pretreatment blocked the late response, but both agents blocked the antigen-induced AHR 24 h later. BAL at 24 h showed no significant differences. These results indicate that only dual responders develop AHR 24 h after antigen challenge. This AHR appears independent of the late increase in sRL or the severity of pulmonary inflammation. AHR appears to be sensitive to agents that interfere with the early release or actions of cyclooxygenase and lipoxygenase metabolites in dual responders.

Role of C fibers in physiological responses to ozone in rats

1995 ◽  
Vol 78 (5) ◽  
pp. 1757-1763 ◽  
Author(s):  
M. Jimba ◽  
W. A. Skornik ◽  
C. R. Killingsworth ◽  
N. C. Long ◽  
J. D. Brain ◽  
...  
Keyword(s):  
Core Body Temperature ◽  
Dynamic Compliance ◽  
Airway Responsiveness ◽  
Pulmonary Mechanics ◽  
Neonatal Rats ◽  
Implanted Electrodes ◽  
C Fibers ◽  
Induced Changes ◽  
Core Body

The purpose of this study was to evaluate the role of C fibers in airway responsiveness after exposure to ozone (O3) in rats. The role of C fibers in the decreases in heart rate (HR) and core body temperature (Tc) that occur after inhalation of O3 was also examined. Neonatal rats were treated with capsaicin (Cap) or the vehicle used to dissolve capsaicin (Veh). Cap has been shown to cause permanent destruction of C fibers. When they reached adulthood, conscious minimally restrained rats were exposed to 2 ppm O3 or to air for 3 h. Two hours after the cessation of exposure, rats were anesthetized and instrumented for the measurement of pulmonary mechanics and airway responsiveness to inhaled aerosolized methacholine. O3 had no effect on baseline pulmonary conductance (GL) in either Veh or Cap rats but did cause a decrease in dynamic compliance (Cdyn) in Cap rats (P < 0.05). In Cap rats, O3 exposure caused a marked increase in airway responsiveness; the doses of inhaled aerosolized methacholine required to decrease GL and Cdyn by 50% were 6.5-fold and 9.8-fold lower in O3-compared with air-exposed rats (P < 0.005). In contrast, in Veh rats, O3 did not alter responsiveness. During O3 exposure, there was a profound, almost 50%, decrease in HR as measured with implanted electrodes. A decrease in Tc (measured with a rectal probe) of approximately 2.5 degrees C also occurred during O3 exposure. There was no significant effect of Cap pretreatment on the magnitude of these O3-induced changes in HR and Tc. Our results are consistent with the hypothesis that C fibers act to inhibit the development of hyperresponsiveness elicited by O3 inhalation but do not contribute to O3-induced changes in HR or Tc.

Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs

1985 ◽  
Vol 58 (4) ◽  
pp. 1347-1353 ◽  
Author(s):  
K. F. Chung ◽  
A. B. Becker ◽  
S. C. Lazarus ◽  
O. L. Frick ◽  
J. A. Nadel ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Airway Responsiveness ◽  
Antigen Challenge ◽  
Pulmonary Resistance

We studied whether antigen-induced airway hyperresponsiveness was associated with pulmonary inflammation in 11 anesthetized ragweed-sensitized dogs. Airway responsiveness to acetylcholine aerosol was determined before and at 2, 6, and 24 h after ragweed or sham aerosol challenge. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) performed at either 2 or 6 h. Total pulmonary resistance increased 11-fold at 5 min after ragweed. Airway responsiveness was unchanged at 2 h but was increased 6.6-fold at 6 h in 8 of 11 dogs (P less than 0.001); hyperresponsiveness persisted from 4 days to 4 mo. Airway responsiveness was unchanged by aerosols of diluent. Neutrophils in BAL fluid increased approximately sixfold at 2 h (P less than 0.02) and at 6 h (P less than 0.02) after antigen challenge. There were fewer eosinophils in fluid recovered at 6 h after antigen compared with 2 h lavages (P less than 0.05). In three nonresponders, BAL showed no significant changes in neutrophils and eosinophils after antigen. Thus antigen-induced hyperresponsiveness is associated with the presence of pulmonary inflammation, presumably arising from the airways and involving both neutrophils and eosinophils.

scholarly journals Age-related increases in ozone-induced injury and altered pulmonary mechanics in mice with progressive lung inflammation

2013 ◽  
Vol 305 (8) ◽  
pp. L555-L568 ◽  
Author(s):  
Angela M. Groves ◽  
Andrew J. Gow ◽  
Christopher B. Massa ◽  
LeRoy Hall ◽  
Jeffrey D. Laskin ◽  
...  
Keyword(s):  
Pulmonary Inflammation ◽  
Tissue Mechanics ◽  
Ozone Exposure ◽  
Surfactant Protein D ◽  
Pulmonary Mechanics ◽  
Alveolar Wall ◽  
Lung Pathology ◽  
Activated Macrophages ◽  
Cell Hyperplasia ◽  
Age Related

In these studies we determined whether progressive pulmonary inflammation associated with aging in surfactant protein D ( Sftpd)−/−mice leads to an exacerbated response to ozone. In Sftpd−/−mice, but not wild-type (WT) mice, age-related increases in numbers of enlarged vacuolated macrophages were observed in the lung, along with alveolar wall rupture, type 2 cell hyperplasia, and increased bronchoalveolar lavage protein and cell content. Numbers of heme oxygenase+ macrophages also increased with age in Sftpd−/−mice, together with classically (iNOS+) and alternatively (mannose receptor+, YM-1+, or galectin-3+) activated macrophages. In both WT and Sftpd−/−mice, increasing age from 8 to 27 wk was associated with reduced lung stiffness, as reflected by decreases in resistance and elastance spectra; however, this response was reversed in 80-wk-old Sftpd−/−mice. Ozone exposure (0.8 ppm, 3 h) caused increases in lung pathology, alveolar epithelial barrier dysfunction, and numbers of iNOS+ macrophages in 8- and 27-wk-old Sftpd−/−, but not WT mice at 72 h postexposure. Conversely, increases in alternatively activated macrophages were observed in 8-wk-old WT mice following ozone exposure, but not in Sftpd−/−mice. Ozone also caused alterations in both airway and tissue mechanics in Sftpd−/−mice at 8 and 27 wk, but not at 80 wk. These data demonstrate that mild to moderate pulmonary inflammation results in increased sensitivity to ozone; however, in senescent mice, these responses are overwhelmed by the larger effects of age-related increases in baseline inflammation and lung injury.

Acrolein increases airway sensitivity to substance P and decreases NEP activity in guinea pigs

1993 ◽  
Vol 74 (4) ◽  
pp. 1830-1839 ◽  
Author(s):  
C. R. Turner ◽  
R. B. Stow ◽  
S. J. Hubbs ◽  
B. C. Gomes ◽  
J. C. Williams
Keyword(s):  
Substance P ◽  
Bronchoalveolar Lavage ◽  
Guinea Pigs ◽  
Pulmonary Inflammation ◽  
Neutral Endopeptidase ◽  
Vehicle Control ◽  
Pulmonary Mechanics ◽  
Time Points ◽  
Tracheal Tissue ◽  
Airway Responses

The effects of acrolein exposure on airway responses to intravenous substance P were determined in guinea pigs exposed to vehicle or 1.6 ppm acrolein for 7.5 h on 2 consecutive days and examined 1, 4, 8, 15, and 28 days after exposure by use of pulmonary mechanics and bronchoalveolar lavage (BAL). Lung, trachea, liver, and BAL fluid were also assayed for neutral endopeptidase (NEP) activity 1, 7, and 28 days after exposure. Pulmonary inflammation and epithelial damage were prominent 1 day after acrolein exposure. NEP activity was decreased in the lungs, trachea, and liver 1 and 7 days after acrolein. Twenty-eight days after exposure, NEP activity in the lungs and liver was not significantly different in vehicle- and acrolein-exposed guinea pigs but was still reduced in tracheal tissue. The BAL NEP activity in acrolein-exposed guinea pigs was approximately twice that of vehicle control guinea pigs at all three time points. Acrolein caused a prolonged increase in airway sensitivity to substance P. Experiments performed in the presence of thiorphan suggested that the acrolein-induced reduction in NEP may contribute to increased airway sensitivity to aerosolized substance P, but the increase in airway sensitivity to intravenous substance P may occur by additional mechanisms.

Effect of obesity on pulmonary inflammation induced by acute ozone exposure: role of interleukin-6

2008 ◽  
Vol 294 (5) ◽  
pp. L1013-L1020 ◽  
Author(s):  
Jason E. Lang ◽  
Erin S. Williams ◽  
Joseph P. Mizgerd ◽  
Stephanie A. Shore
Keyword(s):  
Bronchoalveolar Lavage ◽  
Tyrosine Phosphorylation ◽  
Leukemia Inhibitory Factor ◽  
Pulmonary Inflammation ◽  
Ozone Exposure ◽  
Epithelial Barrier ◽  
Wild Type ◽  
Isotype Control ◽  
Stat Proteins

To determine the role of interleukin (IL)-6 in the increased ozone (O3)-induced inflammation and injury observed in obese vs. lean mice, lean wild-type and leptin-deficient obese ( ob/ob) mice were injected with anti-IL-6 antibody (Ab) or isotype control Ab 24 h before exposure to either O3 (2 ppm for 3 h) or room air. Four or 24 h after O3 exposure, bronchoalveolar lavage (BAL) was performed, and the lungs were harvested for Western blotting. Anti-IL-6 Ab caused substantial reductions in O3-induced increases in BAL IL-6 in mice of both genotypes. Four hours following O3, ob/ob mice had increased BAL neutrophils compared with controls, and anti-IL-6-Ab virtually abolished this difference. At 24 h, O3-induced increases in BAL protein and BAL serum albumin were augmented in ob/ob vs. wild-type mice, and anti-IL-6 Ab ablated these obesity-related differences in epithelial barrier injury. O3 increased tyrosine phosphorylation of STAT-3 and STAT-1. There was no effect of obesity on STAT-3 phosphorylation, whereas obesity decreased STAT-1 expression, resulting in reduced STAT-1 phosphorylation. IL-6 neutralization did not alter STAT-3 or STAT-1 phosphorylation in ob/ob or wild-type mice. O3 increased BAL leukemia inhibitory factor (LIF) to a greater extent in obese than in lean mice, and LIF may account for effects on STAT phosphorylation. Our results suggest that IL-6 plays a complex role in pulmonary responses to O3, a role that differs between wild-type and ob/ob mice. Moreover, obesity-related differences in activation of STAT proteins may contribute to some of the differences in the response of obese vs. lean mice.

Pulmonary inflammation and epithelial injury in response to acute ozone exposure in the rat

1992 ◽  
Vol 112 (1) ◽  
pp. 64-72 ◽  
Author(s):  
Michael V. Pino ◽  
Jana R. Levin ◽  
Mary Y. Stovall ◽  
Dallas M. Hyde
Keyword(s):  
Pulmonary Inflammation ◽  
Ozone Exposure ◽  
Epithelial Injury

Transgenic overexpression of β2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

2000 ◽  
Vol 279 (2) ◽  
pp. L379-L389 ◽  
Author(s):  
Dennis W. McGraw ◽  
Susan L. Forbes ◽  
Judith C. W. Mak ◽  
David P. Witte ◽  
Patricia E. Carrigan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelium ◽  
Adrenergic Receptors ◽  
Airway Epithelial Cells ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Clara Cell ◽  
Whole Body ◽  
Airway Epithelial

Airway epithelial cells express β2-adrenergic receptors (β2-ARs), but their role in regulating airway responsiveness is unclear. With the Clara cell secretory protein (CCSP) promoter, we targeted expression of β2-ARs to airway epithelium of transgenic (CCSP-β2-AR) mice, thereby mimicking agonist activation of receptors only in these cells. In situ hybridization confirmed that transgene expression was confined to airway epithelium, and autoradiography showed that β2-AR density in CCSP-β2-AR mice was approximately twofold that of nontransgenic (NTG) mice. Airway responsiveness measured by whole body plethysmography showed that the methacholine dose required to increase enhanced pause to 200% of baseline (ED200) was greater for CCSP-β2-AR than for NTG mice (345 ± 34 vs. 157 ± 14 mg/ml; P < 0.01). CCSP-β2-AR mice were also less responsive to ozone (0.75 ppm for 4 h) because enhanced pause in NTG mice acutely increased to 77% over baseline ( P < 0.05) but remained unchanged in the CCSP-β2-AR mice. Although both groups were hyperreactive to methacholine 6 h after ozone exposure, the ED200for ozone-exposed CCSP-β2-AR mice was equivalent to that for unexposed NTG mice. These findings show that epithelial cell β2-ARs regulate airway responsiveness in vivo and that the bronchodilating effect of β-agonists results from activation of receptors on both epithelial and smooth muscle cells.

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