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Rheumatology Advance Access published online on June 18, 2007
Rheumatology, doi:10.1093/rheumatology/kem117
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Characterization of haemorrhagic pulmonary capillaritis: another manifestation of Pristane-induced lupus

V. R. Chowdhary, J. P. Grande1, H. S. Luthra and C. S. David2

Division of Rheumatology, Department of Medicine, 1Division of Laboratory Medicine and Pathology and 2Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence to: Chella S. David, PhD, Professor of Immunology, Department of Immunology, Mayo Clinic College of Medicine, 200, 1st SW Rochester, MN 55905, USA. E-mail: davic4{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Pristane-induced lupus is a well-established model of murine lupus. Mice injected with Pristane develop lupus-specific autoantibodies and glomerulonephritis. A chance observation led us to identify and characterize haemorrhagic pulmonary capillaritis in Pristane-injected mice.

Methods. Eight-week-old C57Bl/10 (B10, H-2b) mice received a single intraperitoneal injection of 0.5 ml of Pristane. Control mice received phosphate-buffered saline (PBS) injection. Mice were bled at 2 weeks after Pristane injection and monthly thereafter for serology and for antinuclear antibody (ANA). To characterize pulmonary disease, bronchoalveolar lavage (BAL) was carried out for total and differential cell count. Cytokines levels were checked for IL-2, IL-4, TNF-{alpha}, IFN-{gamma}, IL-6 and IL-10. Lungs were examined by histopathology and electron microscopy.

Results. All mice injected with Pristane developed a pulmonary capillaritis with perivascular infiltration with macrophages, neutrophils, lymphocytes and eosinophils. In addition, alveoli showed macrophage and neutrophil infiltration. The degree of perivascular and alveolar inflammation was moderate to severe. BAL was inflammatory with cell composition of macrophages, neutrophils, lymphocyte and eosinophils. There was evidence of endothelial injury on electron microscopy but no evidence of immune complex deposition. IL-6 and IL-10 were increased in BAL but levels of TNF-{alpha}, IFN-{gamma}, IL-2 and IL-4 were not. Anti-neutrophil cytoplasm antibody (ANCA) was negative. Kidneys demonstrated an increase in mesangial matrix and cellularity compatible with WHO Class II lupus lesion. There were immune complexes and complement deposition in the kidney. There were oil granulomas in peritoneum, spleen and liver but no evidence of vasculitis in these organs was seen.

Conclusion. The relative ease and high penetrability of lesion makes it an attractive model to study pulmonary vasculitis.

KEY WORDS: Pristane induced lupus, pulmonary vasculitis


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 Acknowledgements
 References
 
Pristane-(2,6,10,14-tetramethylpentadecane)-induced lupus is a well-established model of ‘environmentally’ induced murine lupus [1,2]. Unlike Pristane-induced plasmacytoma and arthritis that occur only in DBA/1 and BALB/c, there is a widespread strain susceptibility to Pristane-induced lupus [3]. BALB/c, SJL and virtually all mice strains are susceptible. Nonetheless, the spectrum of autoantibodies and clinical manifestations differ from strain to strain [3]. Pristane-induced lupus is characterized by the presence of anti-nuclear ribonucleoprotein/Sm (anti-nRNP/Sm), anti-ribosomal P, anti-Su, anti-chromatin and anti-single and double-stranded DNA (ssDNA and dsDNA, respectively) antibodies [1].

The mechanism of Pristane-induced autoantibody production is still incompletely understood and possibly involves distinct pathways with different T cell and cytokine requirements. Pristane treatment of athymic mice results in augmentation of IgM, IgG anti-ssDNA and anti-chromatin antibodies, which are spontaneously produced in these mice, suggesting a T-independent effect. In contrast, athymic mice fail to produce anti-nRNP/Sm and Su autoantibodies either spontaneously or upon Pristane treatment suggesting a differential requirement for T cell help for different autoantibody specificities [4]. The observation that induction of anti-dsDNA/chromatin antibodies by Pristane is abrogated in mice lacking interleukin 6 (IL-6) or interferon gamma (IFN-{gamma}) [5,6], whereas the anti-RNP/Sm autoantibody frequency is markedly reduced in IFN-{gamma}-deficient mice, but not in IL-6-deficient strains, underscores the complexities of autoantibody induction by Pristane.

A diffuse proliferative glomerulonephritis is induced by Pristane in Balb/C and SJL mice [2,7]. Pristane also accelerates dsDNA/chromatin production and renal disease in NZB/NZW mice [8]. In Balb/C and SJL mice, ds-DNA antibodies do not cause the renal lesions because the antibodies appear later in the course and after establishment of renal disease. Renal disease is possibly cytokine mediated as interleukin-12 knockout (IL-12–/–) and IFN-{gamma} knockout (IFN-{gamma}–/–) mice are protected from nephritis after Pristane treatment, IL-6–/– mice develop a milder form of renal disease [5], while absence of IL-4 has no effect on development of renal disease [6,9]. The severity of nephritis in Fc{gamma}R II–/– mice is enhanced [10].

Even though Pristane-induced lupus is a systemic disease, extrarenal, especially the pulmonary involvement, has not been very well described. Alveolar haemorrhage as a complication after Pristane injection has been alluded to earlier in 10–50% of mice [11]. However, the histopathology and the pathogenesis have not been adequately addressed. The aim of this study was to characterize pulmonary manifestation of Pristane-induced lupus.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 Acknowledgements
 References
 
Mice
Eight-week-old C57Bl/10 (B10, H-2b) mice received a single intraperitoneal injection of 0.5 ml of Pristane. Control mice received phosphate-buffered saline (PBS) injection. All mice used in this study were bred and maintained in the pathogen-free immunogenetics mouse colony at Mayo Clinic (Rochester, MN, USA) and cared for as per institutional animal care and use committee protocol. The institutional animal care and use committee of the Mayo clinic approved the protocol for this study. Mice were bled at 2 weeks after Pristane injection and monthly thereafter for serology.

Bronchoalveolar lavage (BAL)
To characterize pulmonary disease, BAL was carried out as described earlier [12] at day 14. Six mice were injected with Pristane and five with PBS. Briefly, mice were anaesthetized with Avertin solution (2,2,2-tribromoethanol, Aldrich Chemical Co., Milwaukee, WI, USA) and the tracheae were cannulated. BAL fluids were collected with three separate 1 ml sterile PBS washes of lung via the trachea of each mouse. Cells were washed once with PBS by centrifugation at 1400g for 10 min and the supernatants were stored at –20°C for cytokine analysis. The cell pellets were re-suspended in 1 ml PBS. Total cells in BAL fluids were determined for each sample with a standard haemocytometer.

Cytokine levels in BAL
Quantification of IL-2, IL-4, IL-6, IL-10, TNF-{alpha} and IFN-{gamma} was performed by sandwich enzyme-linked immunoabsorbent assay (ELISA) as described previously [12]. Assays were performed in 96-well flat-bottom micro titre plates (Immulon 2, Dyna tech Laboratories, Chantilly, VA, USA). Plates were incubated with primary antibody solution 2 µg/ml, for IL-2, IL-6, IL-10, IFN {gamma}, 4 µg/ml for IL-4 and 25 µg/ml for TNF-{alpha}, in 0.1 M sodium phosphate buffer at 4°C overnight (BD Biosciences Pharmingen, San Diego, CA, USA).

Anti-nuclear antibody (ANA)
ANA was done by a standard protocol as described previously [13] using Hep-2 cells as substrate. Images were captured on an LSM 510 laser scanning confocal microscope (Carl Zeiss, Inc., Heidelberg, Germany) equipped with an Axiovert 100 M inverted microscope stage. A 63xC-Apochromat water immersion objective lens (1.2 na) was used. Excitation was with the 488 nm line from an argon ion laser. Emission was collected through a 505 nm long pass filter.

Lung histology
In a separate group of mice, five were injected with Pristane and four received PBS. Lungs were inflated with 0.5 ml of 10% neutral-buffered formalin, and fixed overnight. The fixed tissue samples were embedded in paraffin and 4-µm thick sections prepared by the Pathology Department of the Mayo Clinic and stained with H&E. The sections were read by an experienced mouse pathologist (J.P.G.). Scoring of pulmonary inflammation was based on a method published previously [14]. Four to five vessels were assessed per mouse. Briefly for each vessel, two characteristics of the perivascular infiltrate were assessed. The perimeter score represented percentage of vessel perimeter surrounded by cells. A score of one represented 5–20% of perimeter surrounded by cells, 25–45% of vessel surrounded by infiltrate received a score of 2. Three points were given for 50–75% and 4 for 75–100% of vessel surrounded by cells. The depth of the inflammatory infiltrate was measured as well.

Immunofluorescence
Immune complex deposition in kidneys was examined by direct immunofluorescence using protocol described earlier [15]. Unfixed cryostat sections were blocked for 30 min with 5% body surface area (BSA) in PBS and incubated for 60 min with FITC-conjugated goat anti-mouse IgG and anti-mouse C3 (ICN/Cappel, Aurora, OH, USA) in PBS (pH 7.2) containing 5% BSA. Stained sections were washed three times in PBS for 15 min each time and examined by fluorescence microscopy.

Electron microscopy
Lung and kidney tissue was fixed in Trump's fixative (1% glutaraldehyde and 4% formaldehyde in 0.1 M phosphate buffer, pH 7.2) [16]. It was rinsed for 30 min in three changes of 0.1 M phosphate buffer, pH 7.2, followed by a 1 h postfix in phosphate-buffered 1% OsO4. After rinsing in three changes of distilled water for 30 min, the tissue was en bloc stained with 2% uranyl acetate for 30 min at 60°C. It was then rinsed in three changes of distilled water, dehydrated in progressive concentrations of ethanol and 100% propylene oxide and embedded in Spurr's resin [17]. Thin (90 nm) sections were cut on a Reichert Ultracut E ultramicrotome, placed on 200 mesh copper grids and stained with lead citrate. Micrographs were taken on a JEOL 1200 EXII operating at 60 kV.

Statistical analysis
Statistical analysis was carried out by Wilcoxon's rank sum test using SAS software (version 9, SAS institute, Cary, NC, USA). A P-value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 Acknowledgements
 References
 
The current study was aimed at studying the pulmonary effects of Pristane. All mice were asymptomatic and only one pristane injected mouse died at day 30.

Inflammatory cells in BAL of Pristane-treated mice
The BAL fluid collected from Pristane, but not PBS-treated mice were consistently haemorrhagic. The composition of BAL fluid at day 14 in Pristane-injected mice is shown in Fig 1. The total cellularity of BAL was 76 ± 51.3 x 104/ml, macrophages 42.8 ± 19.4 x 104/ml, lymphocytes 5.1 ± 6.8 x 104/ml, neutrophils 15.5 ± 18.8 x 104/ml and eosinophils 12.8 ± 28.1 x 104/ml. In the PBS-injected mice, total number of cells was which was chiefly macrophages was 29.6 ± 14.2 x 104/ml.


Figure 1
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  		FIG. 1. Composition of bronchoalveolar lavage fluid in Pristane- and PBS-injected mice. Pristane-injected mice had a highly cellular lavage fluid consisting of macrophages, neutrophils, eosinophils and lymphocytes. In PBS-injected mice, BAL was composed of only macrophages. The difference between neutrophils numbers in Pristane-injected vs PBS-injected mice was statistically significant (P = 0.004) whereas the total number of cells (P = 0.082), macrophages (P = 0.33), lymphocytes (P = 0.082) and eosinophils (P = 0.18) were not. Values represent average with bars showing standard error of mean. Data are pooled from two experiments on 5–6 mice.

 
The cellularity was markedly increased and consisted of macrophages, lymphocytes, neutrophils and eosinophils (Fig. 2, panels A and B). The difference in neutrophil numbers between Pristane and PBS-injected mice was statistically significant (P = 0.004), whereas the difference in the total number of cells (P = 0.082), macrophages (P = 0.33), lymphocytes (P = 0.082) and eosinophils was not (P = 0.18). The lack of statistical significance stems from a combination of the small sample size and the possibility that some of the highest values may be outliers. However, the macrophages in Pristane-injected mice were qualitatively different and appeared larger and full of oil globules as compared with PBS-injected mice. Presence of lipid granules in macrophages was confirmed by staining with oil red O (Fig. 2, panel C)


Figure 2
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  		FIG. 2. Composition of bronchoalveolar lavage fluid (haematoxylin and eosin, x40). In Pristane-injected mice (panel B), BAL was highly cellular with macrophages, neutrophils, lymphocytes and eosinophils. The macrophages in Pristane-injected mice (panel B) were larger and contained oil globules (arrow) as compared with PBS-injected mice (panel A). These macrophages stained red with the stain oil red 0 indicative of lipoid material in them (arrowhead panel C).

 
Elevated IL-6 and IL-10 in BAL of Pristane-injected mice
The predominant cytokines in BAL were IL-6 and IL-10 (Fig. 3) at day 14. The mean levels of IL-6 and IL-10 in Pristane-injected mice were 156.13 pg/ml and 130.98 pg/ml, respectively, and 9.21 pg/ml and 1.47 pg/ml, respectively, in PBS mice. Levels of IL-6 in B10 Pristane-injected mice were statistically higher than PBS-injected mice (P = 0.002) as well as levels of IL-10 (P = 0.002). There was no difference in the levels of TNF-{alpha} (P = 0.93) and IFN-{gamma} (P = 0.33). No IL-2 or IL-4 could be detected in any groups.


Figure 3
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  		FIG. 3. Cytokines in BAL in Pristane-and PBS-injected mice. Pristane-injected mice had high levels of IL-6 (P = 0.002) and IL-10 (P = 0.002) as compared with PBS-injected mice. The levels of TNF-{alpha} and IFN-{gamma} were not different between the groups. No IL-2 or IL-4 could be detected in BAL. Values are means with bars showing standard error of mean. Data are pooled from two experiments on 5–6 mice.

 
Lung histopathology showed perivascular infiltrates and evidence of pulmonary haemorrhage
The histopathology of the lung at day 14 showed areas of focal haemorrhages. There was a severe mixed inflammatory infiltrate of lymphocytes, plasma cells, polymorphonuclear leucocytes, macrophage and occasional eosinophil surrounding the capillaries and venules in all the mice (Fig 4A). There was invasion of the vessel wall with the infiltrate. Focal peribronchial infiltrate with plasma cells and lymphocytes was seen. Interstitium and alveolar spaces showed haemosiderin-laden macrophages (Fig. 4B). There was giant cell inflammation seen around the oil droplets (Pristane?). Severity of the inflammation was uniform throughout all lobes in an individual mouse. The perimeter score 3.8 (range 2–4). The width of the inflammatory infiltrate varied from 2 to 6 cell-layers thick (30–66 µm). The size of the vessel between PBS- and Pristane-injected mice was similar. There was no vasculitis in mice injected with PBS (Fig. 4E)


Figure 4
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  		FIG. 4. Histopathology of lung in Pristane-injected mice. Panel A shows lung (H and E, x40) tissue demonstrating perivascular inflammation at day 14. The inflammatory infiltrate was composed of macrophages, neutrophils, lymphocytes and eosinophils. Panel B shows haemosiderin-laden macrophages (white arrow) with only mild perivascular inflammation at 5 months after Pristane injection. Electron microscopy in panel C demonstrated oil droplets in macrophages (dark arrow) even up to 5 months after intraperitoneal Pristane and severe endothelial injury with perivascular inflammatory infiltrate (arrow, panel D). Panel E shows normal lung histopathology in mice injected with PBS at day 14.

 
Electron microscopy showed endothelial injury and oil granulomas
Electron microscopy of the lung showed severe endothelial injury at day 14. The alveolar basement membrane was intact. The macrophages were laden with lipid droplets (Pristane?) (Fig. 4C). The perivascular inflammatory infiltrate was obvious (Fig. 4D). There were no immune complexes either in the endothelial cells or within the alveolar basement membrane.

Spleen, liver, kidney and peritoneum had oil granulomas but no vasculitis
Peritoneum showed extensive granulomas by day 14 (Fig 5, panel A). Spleen showed follicular hyperplasia and oil granulomas (Fig. 5B). Liver showed periportal oil granulomas (Fig. 5C). Kidneys showed a mild increase in mesangial matrix and cellularity. The lesions were similar to WHO class II lesions of human lupus (Fig 5D). Indirect immunofluorescent staining showed segmental granular mesangial staining by both IgG and C 3. (Fig. 5E and F). Electron microscopy of the kidneys showed increase in mesangial matrix and cellularity. Immune complex deposition was seen in mesangial regions of glomeruli (data not shown). No vasculitis was seen in spleen, kidney or liver.


Figure 5
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  		FIG. 5. Histopathology (H and E, x40) of peritoneum showed oil granuloma (panel A) at day 14. Spleen showed follicular hyperplasia (panel B) and liver showed minimal periportal inflammation (panel C) and oil granuloma at day 14. Panel D (H and E, x40) demonstrates kidney with mild increase in mesangial matrix and cellularity in Pristane-injected mice. Immunofluorescent staining with FITC-conjugated goat anti-mouse IgG (panel E) and anti-mouse C3 (panel F) showed segmental granular mesangial positive staining.

 
Pristane-injected mice develop anti-nuclear antibodies (ANAs)
These mice developed ANAs in 4/11 sera. The ANA patterns seen were speckled (one mouse, Fig. 6A), rim (two mice, Fig. 6B) and cytoplasmic (one mouse, Fig. 6C). Further serological characterization of reactivity is under way. Preliminary data from western blot against WEHI cells showed reactivity against U170k protein. The sera of mice were tested for reactivity to lung, kidney and salivary gland extracts and compared with the MRL and SNF sera reactivity. No specific reactivity could be found for lung extracts in these mice. Sera of four mice with pulmonary capillaritis were tested for anti-neutrophil cytoplasm antibody (ANCA) and were negative.


Figure 6
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  		FIG. 6. ANA (Immunofluorescence): antinuclear antibodies were seen in 4 of 11 mice injected with Pristane. The pattern of immunofluorescence was speckled (panel A), rim (panel B) and cytoplasmic (panel C).

 

   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
Acknowledgements
 References
 
Intraperitoneal injection of Pristane, a mineral oil readily induces a spectrum of autoantibodies, which is accompanied by renal pathology in several strains of mice. Pristane-induced lupus is therefore used as a model of environmentally induced lupus. Nonetheless, pulmonary pathology induced by Pristane has not been described before. We have shown the relative ease and high penetrability of pulmonary capillaritis in B10 (H-2b) mice. After intraperitoneal injection, Pristane could be detected in blood and various body tissues in sufficient amounts to interact with resident cells [18]. Phagocytosed Pristane, persisting in the macrophages-induced granulomatous inflammation in peritoneum, spleen and in liver. Even in the current study, Pristane-laden macrophages could be readily demonstrated in BAL fluid as well as in the lung interstitium. Similar to the granulomatous reaction, Pristane-activated macrophages in the lungs possibly produced several pro-inflammatory cytokines/chemokines resulting in recruitment of other inflammatory mediators culminating in lung pathology. Presence of high numbers of lymphocytes, neutrophils and eosinophils in the BAL along with elevated levels of pro-inflammatory cytokines namely IL-6 and IL-10 support our hypothesis. IL-6 levels are increased in other Pristane-induced diseases like glomerulonephritis [5,19] and arthritis [20] as well. We also found elevated level of IL-10 in BAL from Pristane-treated mice. IL-10 could potentially play a role in lung inflammation. Localized elevation of IL-10 in lung enhances lung fibrosis [21,22] and susceptibility to post-influenza pneumonia due to reduced neutrophil function [23]. Increased expression of IL-10 in pancreas in a transgenic mouse model [24] caused pancreatic infiltration by macrophages initially, followed by lymphocytes. The endothelial cells in this model were highly activated with up-regulation of vascular addressins. We postulate that elevated IL-10 in BAL in our mice contributed to massive infiltration with predominantly macrophages and consequent tissue injury. IL-10 has several pathogenic effects in systemic lupus erythematosus (SLE) [25–29]. In a small trial, treatment of a small group of SLE patients with anti-IL10 resulted in an improvement of their cutaneous vasculitis and arthritis and skin rash [30].

Pulmonary haemorrhage in SLE patients is presumed to be immune complex-mediated based on presence of high circulating dsDNA, circulating immune complexes, low serum complement C3 and depositions of immune complexes on EM [31–33]. How the immune complexes mediate lung damage is not known since immunofluorescent studies show that these deposits are poor in complement. Moreover, pulmonary haemorrhage in SLE can occur in absence of immune complex deposition or pulmonary capillaritis [34,35]. In our study, we did not find any immune complexes on EM. Immunopatholgy in absence of immune complexes has been demonstrated in experimental models of serum sickness in rabbits [36]. Pulmonary capillaritis in ANCA-associated vasculitis like Wegener's with similar pathology is poor in immune complexes as well [37].

In contrast to previous report, we found milder WHO class II lesions in the kidney. Diffuse proliferative glomerulonephritis is seen in BALB/C and SJL mice and has not been described in B10 mice. The autoantibodies induced by Pristane are dependent upon the mouse strain and the housing conditions [3,8]. It is likely that the end organ pathology differs and is modulated by strain and housing conditions as well.

In conclusion, Pristane induces haemorrhagic pulmonary capillaritis with relative ease in mice. Lung histopathology demonstrates predominant macrophage-mediated inflammation. There is evidence of endothelial injury and elevated levels of IL-6 and IL-10. This is an attractive model to study pulmonary vasculitis due to its high penetrability and non-fatal nature.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Acknowledgements
References
 
We are grateful to Dr U. S. Deshmukh and Dr S. M. Fu for help with immunoblotting. ANCA testing was done in Dr Ulrich Specks's laboratory. Dr E. Marietta, Mr James Tarara and Mr Jon Charlesworth helped with the cytokine assays, immunofluorescence and electron microscopy, respectively. Mrs Cynthia Crowson carried out statistical analysis. We also thank Dr T. Paisansinsup and Dr G. Rajagopalan for their ideas and advice.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 25 January 2007; revised version accepted 27 March 2007.
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