TOXICOLOGICAL SCIENCES 113(1), 267–277 (2010) doi:10.1093/toxsci/kfp222 Advance Access publication October 1, 2009 Diesel Exhaust Particles in the Lung Aggravate Experimental Acute Renal Failure Abderrahim Nemmar,* ,1 Suhail Al-Salam,† Shaheen Zia,* Javed Yasin,‡ Isehaq Al Husseni,§ and Badreldin H. Ali§ *Department of Physiology, †Department of Pathology, and ‡Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates 17666; and §Department of Pharmacology and Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, 123 Sultanate of Oman 1 To whom correspondence should be addressed at Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates. Fax: þ9713 7671966. E-mail: [email protected]. Received May 11, 2009; accepted September 14, 2009 Inhaled particles are associated with pulmonary and extrapulmo- nary effects. Also, acute renal failure (ARF) is associated with increased mortality, related to pulmonary complications. Here, we tested the possible potentiating effect of diesel exhaust particles (DEP) in an animal model of ARF induced by a single ip injection of cisplatin (CP, 6 mg/kg) in rats. Six days later, the rats were intratracheally instilled with either DEP (0.5 or 1 mg/kg) or saline (control) and renal, systemic, and pulmonary variables were studied 24 h thereafter. CP increased the serum concentrations of urea and creatinine and reduced glutathione (GSH) concentration and superoxide dismutase activity in renal cortex. CP caused renal tubular necrosis; increased urine volume, protein concentrations, and N-acetyl-b-D-glucosaminidase (NAG) activity; and decreased urine osmolality. The combination of DEP and CP aggravated the CP-induced effects on serum urea and creatinine, urine NAG activity, and renal GSH. The arterial O 2 saturation and PO 2 were significantly decreased in CP 1 DEP versus CP 1 saline and CP 1 DEP versus DEP. The number of platelets was reduced in DEP compared to saline-treated rats and CP 1 DEP versus DEP alone or CP 1 saline. Increases in macrophage and neutrophils numbers in bronchoalveolar lavage were found in DEP versus saline group and CP 1 DEP versus CP. Histopathological changes in lungs of DEP- treated rats were aggravated by the combination of CP 1 DEP. These included marked interstitial cell infiltration and congestion. We conclude that the presence of DEP in the lung aggravated the renal, pulmonary, and systemic effects of CP-induced ARF. Key Words: air pollution; diesel exhaust particles; lung inflammation; acute renal failure. Acute renal failure (ARF) is increasingly becoming more frequent and is associated with high costs and adverse clinical outcomes, including excess mortality, increased length of hospital stay, and the requirement for chronic dialysis in survivors (Hoste and Schurgers, 2008; Pannu et al., 2008). Several studies have reported consistent association between ARF and dysfunction of extrarenal organs, particularly the lungs (Hoke et al., 2007; Pierson, 2006;). Experimentally, ARF resulting from either ischemia or bilateral nephrectomy has been reported to cause lung inflammation (Hoke et al., 2007). Furthermore, it has been recently demonstrated that the kidney plays an important role in the production and elimination of mediators of pulmonary injury and that prolonged exposure to these mediators contributes to pulmonary injury (Grigoryev et al., 2008; Hoke et al., 2007). Ischemia and toxicity are considered the main pathophysi- ological factors that lead to the development of ARF (Ali and Al Moundhri, 2006; Ali et al., 2007; Grigoryev et al., 2008; Hoke et al., 2007). A substance that is well known to induce toxic kidney injury is cisplatin (CP). CP is a potent anticancer drug that is commonly used against multiple solid human cancers, including testicular, cervical, ovarian, head, and neck malignancies. The drug is bioactivated to a nephrotoxicant and is also known to produce proximal tubular injury, which is thought to be due to a combination of direct cytotoxicity, intrarenal vasoconstriction, and oxidative stress (Ali and Al Moundhri, 2006; Ali et al., 2007, 2008). Inhaled particulate air pollution with particle diameter less than 2.5 lm contributes to respiratory and cardiovascular morbidity and mortality (Kunzli et al., 2005; Pekkanen et al., 2002; Peters et al., 2001; Pope et al., 2002). Diesel exhaust particles (DEP), which are the major contributors to PM 2.5 and ultrafine particles (diameter 0.1 lm) in cities, have been identified in a number of epidemiological studies to cause adverse health effects, including cardiorespiratory diseases, particularly in individuals with preexisting disease (Atkinson et al., 2001; Pope et al., 1992). Experimental exposure to DEP causes systemic and inflamma- tory response in the airways and impairs the regulation of vascular tone and endogenous fibrinolysis in healthy human volunteers (Mills et al., 2005, 2007; Salvi et al., 1999). Moreover, we (Nemmar and Inuwa, 2008; Nemmar et al., 2003a,b, 2004a, 2007) and others (Inoue et al., 2005, 2006) have reported that exposure to DEP cause pulmonary inflammation and thrombotic complication in hamsters and mice. Ó The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected]at Sultan Qaboos University on January 18, 2011 toxsci.oxfordjournals.org Downloaded from
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TOXICOLOGICAL SCIENCES 113(1), 267–277 (2010)
doi:10.1093/toxsci/kfp222
Advance Access publication October 1, 2009
Diesel Exhaust Particles in the Lung Aggravate Experimental AcuteRenal Failure
Abderrahim Nemmar,*,1 Suhail Al-Salam,† Shaheen Zia,* Javed Yasin,‡ Isehaq Al Husseni,§ and Badreldin H. Ali§
*Department of Physiology, †Department of Pathology, and ‡Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates
University, Al Ain, United Arab Emirates 17666; and §Department of Pharmacology and Clinical Pharmacy, College of Medicine & Health Sciences, Sultan
Qaboos University, Muscat, 123 Sultanate of Oman
1 To whom correspondence should be addressed at Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University,
PO Box 17666, Al Ain, United Arab Emirates. Fax: þ9713 7671966. E-mail: [email protected].
Received May 11, 2009; accepted September 14, 2009
Inhaled particles are associated with pulmonary and extrapulmo-
nary effects. Also, acute renal failure (ARF) is associated with
increased mortality, related to pulmonary complications. Here, we
tested the possible potentiating effect of diesel exhaust particles
(DEP) in an animal model of ARF induced by a single ip injection of
cisplatin (CP, 6 mg/kg) in rats. Six days later, the rats were
intratracheally instilled with either DEP (0.5 or 1 mg/kg) or saline
(control) and renal, systemic, and pulmonary variables were studied
24 h thereafter. CP increased the serum concentrations of urea and
creatinine and reduced glutathione (GSH) concentration and
superoxide dismutase activity in renal cortex. CP caused renal
tubular necrosis; increased urine volume, protein concentrations,
and N-acetyl-b-D-glucosaminidase (NAG) activity; and decreased
urine osmolality. The combination of DEP and CP aggravated the
CP-induced effects on serum urea and creatinine, urine NAG
activity, and renal GSH. The arterial O2 saturation and PO2 were
significantly decreased in CP1 DEP versus CP1 saline and CP1DEP versus DEP. The number of platelets was reduced in DEP
compared to saline-treated rats andCP1DEP versus DEP alone or
CP 1 saline. Increases in macrophage and neutrophils numbers in
bronchoalveolar lavage were found in DEP versus saline group and
CP 1 DEP versus CP. Histopathological changes in lungs of DEP-
treated rats were aggravated by the combination of CP 1 DEP.
These included marked interstitial cell infiltration and congestion.
We conclude that the presence of DEP in the lung aggravated the
renal, pulmonary, and systemic effects of CP-induced ARF.
Key Words: air pollution; diesel exhaust particles; lung
inflammation; acute renal failure.
Acute renal failure (ARF) is increasingly becoming more
frequent and is associated with high costs and adverse clinical
outcomes, including excess mortality, increased length of
hospital stay, and the requirement for chronic dialysis in
survivors (Hoste and Schurgers, 2008; Pannu et al., 2008).
Several studies have reported consistent association between
ARF and dysfunction of extrarenal organs, particularly the
lungs (Hoke et al., 2007; Pierson, 2006;). Experimentally, ARF
resulting from either ischemia or bilateral nephrectomy has
been reported to cause lung inflammation (Hoke et al., 2007).
Furthermore, it has been recently demonstrated that the kidney
plays an important role in the production and elimination of
mediators of pulmonary injury and that prolonged exposure to
these mediators contributes to pulmonary injury (Grigoryev
et al., 2008; Hoke et al., 2007).
Ischemia and toxicity are considered the main pathophysi-
ological factors that lead to the development of ARF (Ali and
Al Moundhri, 2006; Ali et al., 2007; Grigoryev et al., 2008;
Hoke et al., 2007). A substance that is well known to induce
toxic kidney injury is cisplatin (CP). CP is a potent anticancer
drug that is commonly used against multiple solid human
cancers, including testicular, cervical, ovarian, head, and neck
malignancies. The drug is bioactivated to a nephrotoxicant and
is also known to produce proximal tubular injury, which is
thought to be due to a combination of direct cytotoxicity,
intrarenal vasoconstriction, and oxidative stress (Ali and Al
Moundhri, 2006; Ali et al., 2007, 2008).
Inhaled particulate air pollution with particle diameter less than
2.5 lm contributes to respiratory and cardiovascular morbidity
and mortality (Kunzli et al., 2005; Pekkanen et al., 2002; Peters
et al., 2001; Pope et al., 2002). Diesel exhaust particles (DEP),
which are the major contributors to PM2.5 and ultrafine particles
(diameter� 0.1 lm) in cities, have been identified in a number of
epidemiological studies to cause adverse health effects, including
cardiorespiratory diseases, particularly in individuals with
preexisting disease (Atkinson et al., 2001; Pope et al., 1992).
Experimental exposure to DEP causes systemic and inflamma-
tory response in the airways and impairs the regulation of
vascular tone and endogenous fibrinolysis in healthy human
volunteers (Mills et al., 2005, 2007; Salvi et al., 1999). Moreover,
we (Nemmar and Inuwa, 2008; Nemmar et al., 2003a,b, 2004a,
2007) and others (Inoue et al., 2005, 2006) have reported that
exposure to DEP cause pulmonary inflammation and thrombotic
complication in hamsters and mice.
� The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.For permissions, please email: [email protected]
affected by saline (Fig. 4A), DEP 0.5 mg/kg (Fig. 4B), or DEP
1 mg/kg (Fig. 4C) treatments. However, in CP þ saline
(Fig. 4D), CP þ DEP 0.5 mg/kg (Fig. 4E), and CP þ DEP 1
mg/kg (Fig. 4F), the renal cortex showed the presence of acute
tubular necrosis with the presence apoptotic cells, tubular
distention with eosinophilic material, interstitial edema, and
congestion. No accumulation of DEP in the different kidney
sections has been observed in animal exposed to DEP. The
staining for the detection of apoptotic cells showed no evidence
of apoptotic cells in the kidneys of saline or DEP groups
(Figs. 5A–C). Apoptotic cells were seen in the kidneys of CP þsaline (Fig. 5D), CP þ DEP 0.5 mg/kg (Fig. 5E), and CP þDEP 1 mg/kg (Fig. 5F). However, there was no significant
difference in the number of apoptotic cells between these three
groups.
The concentration of platinum in the renal cortex of rats
given CP þ saline (3.95 ± 0.17 ppm) was not significantly
different from that in rats treated with CP þ DEP 0.5 mg/kg
(4.07 ± 0.3 ppm) or CP þ DEP 1 mg/kg (4.08 ± 0.09 ppm). No
platinum has been found in the kidneys of rats treated with
saline, DEP 0.5 mg/kg, or DEP 1 mg/kg.
Effect of CP and DEP on Systemic Variables
The exposure of rats to DEP 1 mg/kg slightly but
insignificantly decreased the PaO2 (Fig. 6A). Pretreatment of
rats with CP þ DEP 0.5 mg/kg significantly decreased PaO2
compared to DEP 0.5 mg/kg alone (Fig. 6A). Interestingly, we
found that treatment with CP þ DEP 1 mg/kg significantly
decreased the PaO2 compared to treatment with CP þ saline
and DEP 1 mg/kg alone (Fig. 6A). Nevertheless, no significant
effect on PaCO2 has been observed between saline (39.5 ± 2.8),
DEP 0.5 mg/kg (39.0 ± 4), DEP 1 mg/kg (41.2 ± 1.9), CP þsaline (41.4 ± 1.5), CP þ DEP 0.5 mg/kg (41.0 ± 2.3), or
DEP þ CP (41.2 ± 0.9).
Figure 6B illustrates that rats treated with DEP 1 mg/kg
slightly but insignificantly decreased the arterial O2 saturation
(SaO2) (Fig. 6B). However, we found that treatment with CP þDEP 1 mg/kg significantly decreased the SaO2 compared to
treatment with CP þ saline or to DEP 1 mg/kg alone (Fig. 6B).
Similarly, the hematocrit in group treated with CP þ DEP
1 mg/kg slightly but significantly increased compared to
treatment with CP þ saline or to DEP 1 mg/kg alone (Fig. 6C)
Figure 7 depicts the effect of treatment with saline and CP
with or without DEP on the numbers of leukocytes and
platelets in whole blood. Although the level of significance was
only reached in group treated with CP þ DEP 1 mg/kg (p <0.05), a dose-dependent increase in leukocytes numbers was
observed after exposure of rats to CP þ DEP 0.5 and 1 mg/kg
compared to CP þ saline (Fig. 7A). The numbers of platelets
was affected by the different treatments (Fig. 7B). Both doses
of DEP caused a significant decrease of platelet number
compared to the saline group. On the other hand, treatment
with CP þ saline decreased the platelet number compared to
saline-treated rats. An aggravating effect was seen in CP þDEP 1 mg/kg group in which the number of platelets was
significantly reduced compared to both DEP 1 mg/kg and CP þsaline-treated groups. The different treatments had no signif-
icant effect on the number of red blood cells and hemoglobin
concentrations (data not shown).
Effect of CP and DEP on Pulmonary Variables
Depending on the treatment performed, the cells found in
BAL were primarily macrophages and polymorphonuclear
leukocytes (PMN) (Fig. 8) and no lymphocytes or other cells
were observed microscopically. The pulmonary administration
of DEP resulted in a marked influx of macrophage and PMN in
the lung compared to saline-treated rats. Similarly, CP þ DEP
significantly and dose-dependently increased the numbers of
macrophage (0.5 mg/kg, p < 0.05 and 1 mg/kg, p < 0.005) and
PMN (0.5 mg/kg, p < 0.05 and 1 mg/kg, p < 0.01) compared to
CP þ saline group. Although the numbers of macrophage and
PMN in CP þ DEP group were higher compared to DEP-
treated rats, this difference did not reach statistical significance.
FIG. 2. Reduced GSH (A) and SOD (B) activity in renal cortex, in Wistar
rats treated with saline (control), DEP 1 mg/kg, CP þ saline, or CP þ DEP 1
mg/kg (n ¼ 6). Mean ± SD. Statistical analysis by Newman-Keuls test.