Annexin A1 and lung fibrosis

Annexin A1 is upregulated in epithelial cells and inflammatory cells. In AnxA1 null mice, there were increased inflammation and fibrosis after bleomycin. There was also an increase in TGFbeta, IFN-gamma, and TNF-a.
The study suggests a protective role for endogenous Annexin A1 in lung fibrosis.

References:
BMC Immunol. 2011 Oct 19;12(1):59. [Epub ahead of print]
Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis.
Damazo AS, Sampaio AL, Nakata CM, Flower RJ, Perretti M, Oliani SM.
Abstract
ABSTRACT:

BACKGROUND:
The balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1) is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases.

RESULTS:
Analyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i) the degree of inflammation at day 7; and ii) indexes of fibrosis (assessed by deposition of hydroxyproline in the lung) at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-beta1, IFN-gamma and TNF-alpha generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21) or therapeutically (from day 14 onward), ameliorated both signs of inflammation and fibrosis.

CONCLUSION:
Collectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.

PMID: 22011168 [PubMed - as supplied by publisher]

SPARC in lung fibrosis

A recent study with bone marrow chimera mice suggested that, bleomycin induces inflammation and fibrosis in wild type through TNF synthesis that triggers TGF-β release; TGF-β promotes fibroblasts deposition and regulates TNF synthesis from macrophages.

B: In WT>SPARC KO chimeras, despite a normal parenchyma inflammation, collagen deposition by fibroblasts is greatly reduced and results in milder fibrosis.

C: In SPARC KO>WT chimeras, the inability of SPARC KO macrophages to down-modulate TNF production in response to TGF-β results in exaggerated and persistent inflammation and severe fibrosis.


Reference
Am J Pathol. 2011 Oct 11. [Epub ahead of print]
SPARC Oppositely Regulates Inflammation and Fibrosis in Bleomycin-Induced Lung Damage.
Sangaletti S, Tripodo C, Cappetti B, Casalini P, Chiodoni C, Piconese S, Santangelo A, Parenza M, Arioli I, Miotti S, Colombo MP.
Source
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Abstract
Fibrosis results from inflammatory tissue damage and impaired regeneration. In the context of bleomycin-induced pulmonary fibrosis, we demonstrated that the matricellular protein termed secreted protein acidic and rich in cysteine (SPARC) distinctly regulates inflammation and collagen deposition, depending on its cellular origin. Reciprocal Sparc(-/-) and wild-type (WT) bone marrow chimeras revealed that SPARC expression in host fibroblasts is required and sufficient to induce collagen fibrosis in a proper inflammatory environment. Accordingly, Sparc(-/-) WT chimeras showed exacerbated inflammation and fibrosis due to the inability of Sparc(-/-) macrophages to down-regulate tumor necrosis factor production because of impaired responses to tumor growth factor-β. Hence, the use of bone marrow cells expressing a dominant-negative form of tumor growth factor-β receptor type II under the monocyte-specific CD68 promoter, as a decoy, phenocopied Sparc(-/-) donor chimeras. Our results point to an unexpected dual role of SPARC in oppositely influencing the outcome of fibrosis.
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PMID: 22001347 [PubMed - as supplied by publisher]

CD69 and lung fibrosis

CD69-/- mice exhibited reduced inflammation and fibrosis.

Reference:
Respir Res. 2011 Oct 5;12(1):131. [Epub ahead of print]
Attenuation of lung inflammation and fibrosis in CD69-deficient mice after intratracheal bleomycin.
Yamauchi K, Kasuya Y, Kuroda F, Tanaka K, Tsuyusaki J, Ishizaki S, Matsunaga H, Iwamura C, Nakayama T, Tatsumi K.
Abstract
ABSTRACT:

BACKGROUND:
Cluster of differentiation 69 (CD69), an early activation marker antigen on T and B cells, is also expressed on activated macrophages and neutrophils, suggesting that CD69 may play a role in inflammatory diseases. To determine the effect of CD69 deficiency on bleomycin(BLM)-induced lung injury, we evaluated the inflammatory response following intratracheal BLM administration and the subsequent fibrotic changes in wild type (WT) and CD69-deficient (CD69-/-) mice.

METHODS:
The mice received a single dose of 3 mg/kg body weight of BLM and were sacrificed at 7 or 14 days post-instillation (dpi). Lung inflammation in the acute phase (7 dpi) was investigated by differential cell counts and cytokine array analyses of bronchoalveolar lavage fluid. In addition, lung fibrotic changes were evaluated at 14 dpi by histopathology and collagen assays. We also used reverse transcription polymerase chain reaction to measure the mRNA expression level of transforming growth factor beta1 (TGF-beta1) in the lungs of BLM-treated mice.

RESULTS:
CD69-/- mice exhibited less lung damage than WT mice, as shown by reductions in the following indices: (1) loss of body weight, (2) wet/dry ratio of lung, (3) cytokine levels in BALF, (4) histological evidence of lung injury, (5) lung collagen deposition, and (6) TGF-beta1 mRNA expression in the lung.

CONCLUSION:
The present study clearly demonstrates that CD69 plays an important role in the progression of lung injury induced by BLM.

PMID: 21970554 [PubMed - as supplied by publisher] Free

FIZZ2 and lung fibrosis

A recent study by Dr. Phan and associates of Michigan identified that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis in vivo and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines in vitro.

FIZZ2 deficiency significantly attenuated pulmonary fibrosis in bleomycin model.

FiZZ2 is down stream of IL-13 signaling.  It is unclear whether deletion of FIZZ2 abolishes IL-13 Th2 response.

Reference
[1] Liu, T., et al., J Immunol. 2011 May 20. [Epub ahead of print] PMID 21602491