Cyclophosphamide induced early biochemical changes in lung lavage fluid and alterations in lavage cell function

Venkatesan, Narayanan; Chandrakasan, Gowri

doi:10.1007/bf00175943

Cited by 15 publications

(3 citation statements)

References 39 publications

(41 reference statements)

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“…This could consequently lead to higher levels of GSSG and/or depletion of GSH. Cyclophosphamide can cause lung injury and has also been shown to deplete glutathione stores (11,30,42), increase the generation of reactive oxygen species by alveolar macrophages (12), inhibit prostaglandin E 2 production by macrophages (11), and modulate BAL cell populations (12). Acrolein, a cyclophosphamide metabolite, can also react directly with glutathione, forming irreversible conjugates (18).…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen

Abushamaa¹,

Sporn²,

Folz

2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen. Am J Physiol Lung Cell Mol Physiol 283: L336-L345, 2002. First published March 29, 2002 10.1152/ ajplung.00012.2002-Delayed pulmonary toxicity syndrome after high-dose chemotherapy (HDC) and autologous hematopoietic support occurs in up to 64% of women with advanced-stage breast cancer. Using a similar, but nonmyeloablative, HDC treatment regimen in mice, we found both immediate and persistent lung injury, coincident with marked decreases in lung tissue glutathione reductase activity and accompanied by increases in lung oxidized glutathione, bronchoalveolar lavage (BAL) lipid peroxidation, and BAL total cell counts. Most interestingly, at 6 wk, BAL total cell counts had increased fourfold, with lymphocyte cell counts increasing Ͼ11-fold. A single supplemental dose of glutathione prevented early lung injury at 48 h but showed no lung-protective effects at 6 wk, whereas single doses of other thiol-sparing agents (Ethyol and glutathione monoethyl ester) showed no benefit. These data suggest that this HDC regimen results in acute and persistent lung toxicity, induced in part by oxidative stress, that culminates with an acute lung cellular inflammatory response. Continuous glutathione supplementation and/or attenuation of the delayed pulmonary inflammatory response may prove beneficial in preventing lung toxicity after the use of these chemotherapeutic agents. delayed pulmonary toxicity syndrome; high-dose chemotherapy; lung injury; glutathione BREAST CANCER is the most common type of cancer among women in the United States and is also well known for its high frequency of recurrence. A high-dose chemotherapy (HDC) regimen utilizing cyclophosphamide, cisplatin, and carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] followed by autologous hematopoietic stem cell support has been developed to overcome the recurrence of cancer in these patients (31). Unfortunately, associated with this regimen is a high incidence (39-64%) of pulmonary drug toxicity (40,44). Patients who develop pulmonary drug toxicity frequently manifest symptoms of dyspnea, dry cough, fever, and hypoxemia, which, if left untreated, can be associated with significant mortality and morbidity (31). We have coined the term delayed pulmonary toxicity syndrome (DPTS) to differentiate this late-onset lung toxicity associated with this specific HDC regimen (44). It should be worth emphasizing that DPTS was described in patients undergoing autologous transplant, as contrasted to allogeneic transplant, in which additional factors, such as graft-vs.-host disease and complications due to the immunotherapy regimen, may come into play (16). Whether the pathogenesis of DPTS is part of the spectrum of idiopathic pneumonia syndrome (10) or is a separate entity remains to be determined.All three drugs used for the HDC regimen are known to be cytotoxic to the lung at high doses; however, the mechanism by which these drugs cause lung damage either indi...

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Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen

Abushamaa¹,

Sporn²,

Folz

2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A number of chemicals were shown to affect GSH levels in BALF and plasma. For example, Venkatesan and Chandrakasan (1994) demonstrated that cyclophosphamide caused decreases in GSH in BALF in rats. Hyperoxia produced significant decreases in GSH in BALF in rats (Stenzel et al, 1993).…”

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confidence: 99%

Depletion by Styrene of Glutathione in Plasma and Bronchioalveolar Lavage Fluid of Non-Swiss Albino (NSA) Mice

Carlson

2010

Journal of Toxicology and Environmental Health, Part A

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Styrene is a widely used chemical, but it is known to produce lung and liver damage in mice. This may be related to oxidative stress associated with the decrease in the levels of reduced glutathione (GSH) in the target tissues. The purpose of this study was to investigate the effect of styrene and its primary metabolites R-styrene oxide (R-SO) and S-styrene oxide (S-SO) on GSH levels in the lung lumen, as determined by amounts of GSH in bronchioalveolar lavage fluid (BALF) and in plasma. When non-Swiss albino (NSA) mice were administered styrene (600 mg/kg, ip), there was a significant fall in GSH levels in both BALF and plasma within 3 h. These returned to control levels by 12 h. The active metabolite R-SO (300 mg/kg, ip) also produced significant decreases in GSH in both BALF and plasma, but S-SO was without marked effect. Since GSH is a principal antioxidant in the lung epithelial lining fluid, this fall due to styrene may exert a significant influence on the ability of the lung to buffer oxidative damage.

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“…However, this level of protection was transient, since 2 d of exposure no longer diminished the level of ozone-induced permeability damage. Although the level of cyclophosphamide treatment used in this study did not result in any observable lung damage or inflammation in the absence of ozone exposure (Figures 1 and 3) (Venkatesan & Chandrakasan, 1994), such pretreatment might have interfered with the proliferate repair of ozone-damaged epithelium that begins around 2 d from the onset of exposure (Bassett & BowenKelly, 1986;Choi et al, 1994;Evans et al, 1976).…”

Section: Figure 4 Recoveries Of (A) Neutrophils and (B) Albumin By Bmentioning

confidence: 96%

Inflammatory Cell Availability Affects Ozone-Induced Lung Damage

Bassett¹,

Elbon-Copp²,

Otterbein³

et al. 2001

Journal of Toxicology and Environmental Health, Part A

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Identifying whether or not neutrophils have a role to play in the early stages of acute lung epithelial injury brought about by inhalation of reactive substances continues to be a major area of investigation. In this study, the availability of circulating neutrophils was manipulated by treatment with either cyclophosphamide or rabbit antiserum against rat neutrophils, prior to exposures to air, a single high ozone exposure of 1 or 2 ppm for 3 h, or a continuous exposure to 0.8-1.0 ppm for up to 48 h. Although cyclophosphamide treatment resulted in undetectable levels of neutrophils in the blood, the recovery of tissue marginated-interstitial neutrophils of 1 x 10(6) cells by collagenase tissue digestion was not significantly diminished at the onset of air and ozone exposures. Cyclophosphamide treatment alone did not cause any permeability damage to air-exposed rat lungs, but did ameliorate ozone-induced increases in bronchoalveolar lavage (BAL) neutrophil and albumin recoveries after both short-term and 1 d of continuous ozone exposure. In contrast to cyclophosphamide, antiserum treatment resulted in greater than a 90% decrease in neutrophil recoveries from both blood and lung tissue at the onset of air and ozone exposures. Antiserum treatment also abrogated ozone-induced neutrophil accumulations in lung lavageable spaces following both single and continuous ozone exposures, but did not significantly affect ozone-associated lung permeability damage indicated by unaltered BAL fluid albumin recoveries. These data demonstrated that under experimental conditions when neutrophils remain within lung tissue marginated and interstitial pools, reduction in circulating blood neutrophil availability is associated with a concomitant decrease in ozone-induced lung damage.

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Cyclophosphamide induced early biochemical changes in lung lavage fluid and alterations in lavage cell function

Cited by 15 publications

References 39 publications

Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen

Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen

Depletion by Styrene of Glutathione in Plasma and Bronchioalveolar Lavage Fluid of Non-Swiss Albino (NSA) Mice

Inflammatory Cell Availability Affects Ozone-Induced Lung Damage

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