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Abstract Number: 400

Combination of the Collagen-Induced Arthritis and Organic Dust-Induced Airway Inflammation Models As a Model of Interstitial Lung Disease in Rheumatoid Arthritis

Katherine Janike1, Jill Poole1, Geoffrey M. Thiele2, Michael J. Duryee3, Lynell W. Klassen4, Amy Nelson5, Kristi Warren6, Benjamin Swanson7 and Ted R. Mikuls8, 1Medicine, University of Nebraska Medical Center, Omaha, NE, 2Int Med/Sec of Rheum/Immun, Univ of NE Medical Ctr, Omaha, NE, 3Internal Medicine Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, 4Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 5Department of Medicine, University of Nebrasa Medical Center, Omaha, NE, 6Department of Medicine, University of Nebraska Medical Center, Omaha, NE, 7Department of Pathology, University of Nebraska Medical Center, Omaha, NE, 8Internal Medicine, Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Animal models, bone disease, Lung Disease, mechanisms and rheumatoid arthritis

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Session Information

Date: Sunday, November 5, 2017

Session Title: Rheumatoid Arthritis – Animal Models Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:   Rheumatoid Arthritis (RA) is characterized by extra-articular involvement including interstitial/inflammatory lung disease (ILD).  Whereas the coexistence of RA and ILD is known, mechanisms linking the two conditions are poorly understood.  The objective of this study was to combine an established organic dust extract (ODE) inhalation injury model with the collagen-induced arthritis (CIA) murine model to assess lung and bone/joint inflammatory outcomes.

Methods: Using an established intranasal inhalation protocol, DBA/1J mice were treated with saline or organic dust extract (ODE) daily for 5 weeks. CIA arthritis was induced with collagen emulsified in Freund’s complete adjuvant and injected on Days 1 and 21. Mice (9-10/group; 2 independent experiments) were assigned to 1of 4 groups: 1-Sham (saline injection/saline inhalation); 2-CIA (CIA/saline inhalation); 3-ODE (saline injection/ODE inhalation); 4-CIA+ODE (CIA/ODE inhalation).  Arthritis inflammatory scores were calculated weekly (0-4 range) based on swelling and redness of the hind paw.  Five hours following final ODE, mice were euthanized. Bones, bronchoalveolar lavage fluid (BALF), and lung tissues were collected.

Results: Table depicts experimental outcome results.  Arthritis and histologic inflammatory scores and were increased in CIA+ODE>CIA alone>ODE alone as compared to Sham. Trabecular bone micro-CT analysis showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength to be most pronounced in CIA+ODE.  Evidence of bone deterioration was also found in the CIA, but not ODE or Sham animals.  In contrast, ODE-induced airway neutrophil influx and cytokine/chemokine (TNF-α, IL-6, CXCL1, CXCL2) in BALF were greater in ODE as compared to ODE+CIA.  Similarly, lung pathology showed ODE-induced lymphoid aggregates and alveolar inflammation were increased in ODE>ODE+CIA.  By flow cytometry, ODE increased lung tissue neutrophils and activated CD11c+CD11bhi macrophages to Sham. Comparable trends, but to a lesser degree, were demonstrated in CIA+ODE.  CIA increased lung activated CD11c+CD11bhiairway macrophages as compared to Sham.

Conclusion: This is the first study to explore the interaction between a repetitive inhalant injury and arthritis induction with findings supporting a compartmentalized immune response. The combined exposures (CIA+ODE) resulted in the greatest degree of arthritis and diffuse bone loss.  However, data support a suppression of the lung inflammatory response in the setting of arthritis.  Activation of the lung macrophage during arthritis induction may be responsible for this paradoxical finding. Finally, this co-exposure model could be exploited further and in other murine strains to better understand the pathogenesis and response to potential treatments for RA-ILD.

 

Sham

CIA

ODE

CIA+ODE

Final Arthritis Inflammatory Score (range: 0-4)

0 (0)

1.33 (0.19)

***

0.70 (0.13)

***

1.60 (0.22)

***, ##

Bone mineral density, g/cm3

0.14 (0.006)

0.11 (0.008)

*

0.15 (0.009)

0.09 (0.01)

**, ##

BALF neutrophil count, x 103

8.2 (1.3)

9.0 (3.3)

524 (79)

***, ###

246 (67)

***

BALF IL-6, pg/ml

0 (0)

0 (0)

246 (26)

***, ##

130 (31)

**

BALF TNF-α, pg/ml

0.7 (0.7)

0 (0)

35 (7)

**,#

13 (5)

*

BALF CXCL2, pg/ml

59 (14)

52 (11)

142 (15)

***, #

69 (9)

**

BALF CXCL1, pg/ml

237 (142)

225 (53)

474 (54)

**,##

254 (41)

Lung tissue neutrophil count, x104

6.1 (2.0)

11.1 (2.0)

30.3 (7.5)

***,##

19.8 (1.2)

**

Lung tissue activated macrophage (CD11c+CD11bhi) count, x104

1.3 (0.4)

3.1 (0.7)

*

12.6 (3.1)

**

7.7 (0.9)

**

Statistical significance denoted as asterisks (*p<0.05; **p<0.01, ***p<0.001) vs. Sham. Statistical difference of ODE vs. CIA +ODE denoted as #p<0.05; ##p<0.01, ###p<0.001.

 


Disclosure: K. Janike, None; J. Poole, None; G. M. Thiele, None; M. J. Duryee, None; L. W. Klassen, None; A. Nelson, None; K. Warren, None; B. Swanson, None; T. R. Mikuls, BMS, 2,Ironwood Pharm, 2,Pfizer Inc, 5,NIH, VA, 2.

To cite this abstract in AMA style:

Janike K, Poole J, Thiele GM, Duryee MJ, Klassen LW, Nelson A, Warren K, Swanson B, Mikuls TR. Combination of the Collagen-Induced Arthritis and Organic Dust-Induced Airway Inflammation Models As a Model of Interstitial Lung Disease in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/combination-of-the-collagen-induced-arthritis-and-organic-dust-induced-airway-inflammation-models-as-a-model-of-interstitial-lung-disease-in-rheumatoid-arthritis/. Accessed May 25, 2022.
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