Complement in lung disease

Sarma, Vidya; Huber‐Lang, Markus; Ward, Peter A.

doi:10.1080/08916930600739456

Cited by 58 publications

(46 citation statements)

References 56 publications

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“…Complement cascade is also activated in the three time points of our model. Previous authors have shown that C3 and C5 play a role in asthma pathogenesis, and our observation of a continuous upregulation of complement cascade pathway (C3 and C1q genes) further validates the idea that complement could be a suitable therapeutic target (12,32). Furthermore, an upregulation of all subunits of C1q complex (C1qa, C1qb, and C1qc) was observed in our model throughout the allergen exposure, suggesting that a therapeutic intervention could take place at an earlier stage of the complement cascade, targeting C1q.…”

Section: Discussionsupporting

confidence: 54%

New asthma biomarkers: lessons from murine models of acute and chronic asthma

Valentin

Crahay²,

Garbacki

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

106

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Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the present study was to unveil new mediators in asthma to better understand pathophysiology and propose or validate new potential therapeutic targets. A mouse model of asthma mimicking acute or chronic asthma disease was used to select genes undergoing a modulation in both acute and chronic conditions. Mice were exposed to ovalbumin or PBS for 1, 5, and 10 wk [short-, intermediate-, and long-term model (ST, IT, and LT)], and gene expression in the lung was studied using an Affymetrix 430 2.0 genome-wide microarray and further confirmed by RT-PCR and immunohistochemistry for selected targets. We report that 598, 1,406, and 117 genes were upregulated and 490, 153, 321 downregulated at ST, IT, and LT, respectively. Genes related to mucous secretion displayed a progressively amplified expression during the allergen exposure protocol, whereas genes corresponding to growth and differentiation factors, matrix metalloproteinases, and collagens were mainly upregulated at IT. By contrast, genes related to cell division were upregulated at ST and IT and were downregulated at LT. In this study, besides confirming that Arg1, Slc26a4, Ear11, and Mmp12 genes are highly modulated throughout the asthma pathology, we show for the first time that Agr2, Scin, and Cd209e genes are overexpressed throughout the allergen exposure and might therefore be considered as suitable new potential targets for the treatment of asthma.

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Section: Discussionsupporting

confidence: 54%

New asthma biomarkers: lessons from murine models of acute and chronic asthma

Valentin

Crahay²,

Garbacki

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

106

View full text Add to dashboard Cite

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“…In case of pneumococcal infections, the activation of the classical pathway has been suggested to be a major host-defense mechanism (34). Moreover, classical pathway activities have been detected in the lung and the airway epithelium (35,36). Apart from the naturally occurring Abs, acute-phase proteins such as CRP and serum amyloid P component protein that bind both S. pneumoniae and C1q have been suggested to play a role in complement-mediated immunity against this pathogen (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

An Alternative Role of C1q in Bacterial Infections: FacilitatingStreptococcus pneumoniaeAdherence and Invasion of Host Cells

Agarwal

Ahl

Riesbeck

et al. 2013

The Journal of Immunology

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Streptococcus pneumoniae (pneumococcus) is a major human pathogen, which evolved numerous successful strategies to colonize the host. In this study, we report a novel mechanism of pneumococcal–host interaction, whereby pneumococci use a host complement protein C1q, primarily involved in the host-defense mechanism, for colonization and subsequent dissemination. Using cell-culture infection assays and confocal microscopy, we observed that pneumococcal surface-bound C1q significantly enhanced pneumococcal adherence to and invasion of host epithelial and endothelial cells. Flow cytometry demonstrated a direct, Ab-independent binding of purified C1q to various clinical isolates of pneumococci. This interaction was seemingly capsule serotype independent and mediated by the bacterial surface-exposed proteins, as pretreatment of pneumococci with pronase E but not sodium periodate significantly reduced C1q binding. Moreover, similar binding was observed using C1 complex as the source of C1q. Furthermore, our data show that C1q bound to the pneumococcal surface through the globular heads and with the host cell-surface receptor(s)/glycosaminoglycans via its N-terminal collagen-like stalk, as the presence of C1q N-terminal fragment and low m.w. heparin but not the C-terminal globular heads blocked C1q-mediated pneumococcal adherence to host cells. Taken together, we demonstrate for the first time, to our knowledge, a unique function of complement protein C1q, as a molecular bridge between pneumococci and the host, which promotes bacterial cellular adherence and invasion. Nevertheless, in some conditions, this mechanism could be also beneficial for the host as it may result in uptake and clearance of the bacteria.

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“…In the setting of marked complement activation, it seems likely that the generation of C3a and C5a, each with significant chemotactic activities, contributed to this inflammation. Complement activation products are capable of inducing chemokine release (64,65), and tubular cells can be a major source of chemokine production in vivo (66) and in vitro (66,67). Although the renal pathologic features in Crry-deficient mice have dissimilarities from HUS, it is notable that marked upregulation of CXC and CC chemokines has been observed in human and experimental HUS (31,32), including CXCL1, 5, 9, and 10 and CCL2 and 5, as we observed here.…”

Section: Discussionmentioning

confidence: 99%

Unrestricted C3 Activation Occurs in Crry-Deficient Kidneys and Rapidly Leads to Chronic Renal Failure

Bao¹,

Wang²,

Chang

et al. 2007

Journal of the American Society of Nephrology

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Deficiency of the C3 convertase regulator Crry is embryonic lethal in mice unless C3 also is absent. For evaluation of the effect of local kidney Crry deficiency in the setting of an intact complement system, Crry Ϫ/Ϫ C3 Ϫ/Ϫ mouse kidneys were transplanted into syngeneic C57BL/6 wild-type mice. These Crry-deficient kidneys developed marked inflammatory cell infiltration, tubular damage, and interstitial fibrosis, whereas similar changes were absent in control transplanted kidneys. Strong C3 deposition in the vessels and tubules that correlated significantly with measures of disease supported that complement activation was pathogenic in this model. Microarray studies showed upregulation of a number of chemokine and extracellular matrix genes, which were validated for CCL2 and CXCL10 mRNA and collagen III protein. The functional significance of these pathophysiologic findings was evaluated by removing both native kidneys, so the transplanted kidney alone provided renal function. Within 21 d of transplantation, seven of eight Crry-deficient kidneys in complement-sufficient wild-type hosts failed, compared with two of 13 controls (P ‫؍‬ 0.001), with final blood urea nitrogen levels of 133.9 ؎ 33.0 and 55.6 ؎ 8.3 mg/dl, respectively (P ‫؍‬ 0.015). These data show that mouse Crry is a critical complement regulator in the kidney. When absent, unrestricted complement activation occurs and quickly leads to marked inflammation and progressive renal failure, with features relevant to human diseases with underlying defects in complement regulation, such as hemolytic uremic syndrome.

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Complement in lung disease

Cited by 58 publications

References 56 publications

New asthma biomarkers: lessons from murine models of acute and chronic asthma

New asthma biomarkers: lessons from murine models of acute and chronic asthma

An Alternative Role of C1q in Bacterial Infections: FacilitatingStreptococcus pneumoniaeAdherence and Invasion of Host Cells

Unrestricted C3 Activation Occurs in Crry-Deficient Kidneys and Rapidly Leads to Chronic Renal Failure

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