Review
C-reactive protein and lung diseases

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Abstract

C-reactive protein (CRP), a member of the pentraxin family of plasma proteins, is one of the most distinctive acute phase reactants. In response to inflammation, cell damage or tissue injury, plasma level of CRP rapidly and dramatically increases up to 1000-fold, a phenomenon that has been used for years to monitor infections and many destructive/inflammatory conditions. The magnitude of CRP increase usually correlates with the severity of injury or inflammation and reflects an important physiological role of this interesting but still under-investigated protein. It is now generally accepted that CRP is involved in host defense and inflammation. However, the exact function of this protein in health and disease remains unclear. Many studies have demonstrated that in different pathophysiological conditions CRP might be involved in the regulation of lung function and may participate in the pathogenesis of various pulmonary disorders. The fluctuation of CRP concentrations in both alveolar fluid and serum associated with different pulmonary diseases suggests its important role in lung biology. Discussion of the still controversial functions of CRP in lung physiology and diseases is the main focus of this review.

Introduction

C-reactive protein (CRP), a prototypical acute-phase protein in humans and other animal species, is one of the most frequently used markers of inflammation. CRP is known to be synthesized by liver cells in response to pro-inflammatory cytokines (Marnell et al., 2005). CRP concentrations in blood are typically extremely low in healthy individuals, but may be fast increased after induction of inflammatory response associated with infections, autoimmune and cardiovascular diseases, as well as sepsis and cancer. Raised CRP level can also be a predictor of cardiovascular diseases and is used as a marker of systemic inflammation in various conditions. For instance, after sepsis, acute myocardial infarction or tissue damage, serum levels of CRP elevated in some cases up to 1000-fold within 1–2 days in correlation with the magnitude of tissue injury or the severity of inflammation.

CRP binds to normal cells, including platelets, phagocytes, and others, as well as to dead or damaged cells. When CRP is bound to pathogens or dying/dead cells, it is recognized by a complement component C1q and activates the classical complement pathway or may also stimulate responses from phagocytic cells via the binding to Fcγ receptors (Marnell et al., 2005, Mold et al., 2002a). Thus, CRP can identify a number of pathogens and altered cells and, therefore, induce their removal by the humoral arm of innate immunity. However, the great number of records indicate that CRP has both the destructive, as well as protective effects (Griselli et al., 1999, Torzewski et al., 2000, Zwaka et al., 2001). CRP that may serve as a predictor of cardiovascular risk is involved in the pathogenesis of arteriosclerotic lesions and can increase tissue damage in acute myocardial infarction and other inflammatory diseases (Berton et al., 2003).

Recent observations suggest that a high level of CRP could be involved in the pathogenesis of cancer. For instance, CRP is a systemic biomarker of reduced lung function and a predictive marker in cystic fibrosis and chronic obstructive pulmonary disease that can also serve as a systemic biomarker of lung inflammation. CRP which is produced locally in the lungs in addition to being released by the liver cells is very important as well. However, its exact function in the lungs and the pathways mediating its involvement in different lung pathologies are not revealed.

New mechanistic, systematic and clinical studies are needed to understand the role of CRP in lung function and lung diseases. These findings could have broad implications. If an unusual role of CRP in the pulmonary tissue is confirmed, some of the conventional knowledge regarding the role of CRP in human diseases may require reappraisal.

Section snippets

CRP structure

CRP (PDBs: 1BO9; 1CRV; 1GNH; 1LJ7; 3L2Y; 3PVN) is a protein with an annular pentameric disk shape belonging to the pentraxin protein family. It consists of the cyclical arrangement of five identical non-covalently bound subunits (protomers) set symmetrically around a central pore (Fig. 1) (Gupta et al., 2012, Shrive et al., 1996, Thompson et al., 1999). Each subunit is oriented into two antiparallel β-sheets and binds two Ca++ ions, which participate in the binding of some of its ligands to

Local CRP production in the lung

New studies have recently revealed that LPS induces CRP production in the lung epithelial cell line A549, whereas Atorvastatin (LIPITOR®), an antihyperlipidemic agent that acts by inhibiting cholesterol synthesis, down-regulates LPS-induced CRP expression. These data have demonstrated that statins, including Atorvastatin, ameliorate lung inflammation by regulating CRP production in human lung epithelial cells (Xing et al., 2011). Other studies have revealed an increase in CRP expression and

Protective CRP function in the lungs (acute inflammation)

Deregulated inflammatory processes usually lead to a variety of diseases. Acute lung injury is one of known conditions where incapability to regulate inflammatory response in the lungs causes self-induced tissue injury and loss of organ function. The magnitude of the acute phase response is related to the severity of the inflammation or the extent of tissue injury (Heuertz and Webster, 1997).

Conclusion remarks

In spite of the accumulation of clinical data about potential effects of CRP protein on human physiology, it is important to realize that the function of this remarkable protein remains unclear. A putative role for CRP has frequently been hypothesized; however the functional data to determine potential casual CRP pathways are still needed. Many experimental studies are required to finally clarify how CRP participates in pathophysiology of different lung diseases. It is likely that CRP induction

References (186)

  • S.U. Eisenhardt et al.

    Monomeric C-reactive protein generation on activated platelets: the missing link between inflammation and atherothrombotic risk

    Trends Cardiovasc Med

    (2009)
  • M. Fujita et al.

    C-reactive protein levels in the serum of asthmatic patients

    Ann Allergy Asthma Immunol: Off Publ Am Coll Allergy Asthma Immunol

    (2007)
  • C. Gaboriaud et al.

    The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties

    J Biol Chem

    (2003)
  • W.Q. Gan et al.

    The interactions between cigarette smoking and reduced lung function on systemic inflammation

    Chest

    (2005)
  • E. Giannakis et al.

    Multiple ligand binding sites on domain seven of human complement factor H

    Int Immunopharmacol

    (2001)
  • N.K. Gupta et al.

    The relationship between C-reactive protein and atherosclerosis differs on the basis of body mass index: the Dallas Heart Study

    J Am Coll Cardiol

    (2012)
  • R.M. Heuertz et al.

    Role of C-reactive protein in acute lung injury

    Mol Med Today

    (1997)
  • B.A. Holm et al.

    Surface property changes from interactions of albumin with natural lung surfactant and extracted lung lipids

    Chem Phys Lipids

    (1985)
  • P. Icard et al.

    Utility of C-reactive protein measurements for empyema diagnosis after pneumonectomy

    Ann Thorac Surg

    (1994)
  • W.S. Jewell et al.

    C-reactive protein (CRP) binding to the Sm-D protein of snRNPS. Identification of a short polypeptide binding region

    Mol Immunol

    (1993)
  • S. Kasayama et al.

    Asthma is an independent risk for elevation of plasma C-reactive protein levels

    Clin Chim Acta: Int J Clin Chem

    (2009)
  • T. Khreiss et al.

    Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils

    J Biol Chem

    (2002)
  • H. Kilic et al.

    The relationship between hs-CRP and asthma control test in asthmatic patients

    Allergol Immunopathol (Madr)

    (2012)
  • D.M. Mannino et al.

    Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination

    Am J Med

    (2003)
  • L. Marnell et al.

    C-reactive protein: ligands, receptors and role in inflammation

    Clin Immunol

    (2005)
  • Q. Meng et al.

    Elevated C-reactive protein levels are associated with endothelial dysfunction in chronic cocaine users

    Int J Cardiol

    (2003)
  • V.J. Abernathy et al.

    C-reactive protein inhibits increased pulmonary vascular permeability induced by fMLP in isolated rabbit lungs

    Am J Physiol

    (1996)
  • A. Agrawal et al.

    Overexpressed nuclear factor-kappaB can participate in endogenous C-reactive protein induction, and enhances the effects of C/EBPbeta and signal transducer and activator of transcription-3

    Immunology

    (2003)
  • A. Agrawal et al.

    Topology and structure of the C1q-binding site on C-reactive protein

    J Immunol

    (2001)
  • A. Agrawal et al.

    A C-reactive protein mutant that does not bind to phosphocholine and pneumococcal C-polysaccharide

    J Immunol

    (2002)
  • C. Agusti et al.

    Inflammatory response associated with pulmonary complications in non-HIV immunocompromised patients

    Thorax

    (2004)
  • N. Ahmed et al.

    Transgenic mice expressing rabbit C-reactive protein exhibit diminished chemotactic factor-induced alveolitis

    Am J Respir Crit Care Med

    (1996)
  • S.A. Alavi et al.

    HsCRP in patients with acute exacerbation of chronic obstructive pulmonary disease

    Iranian Red Crescent Med J

    (2011)
  • A. Ani et al.

    Genetic diversity of Mycobacterium tuberculosis complex in Jos, Nigeria

    BMC Infect Dis

    (2010)
  • N.R. Anthonisen et al.

    Hospitalizations and mortality in the Lung Health Study

    Am J Respir Crit Care Med

    (2002)
  • N.R. Anthonisen et al.

    Smoking and lung function of Lung Health Study participants after 11 years

    Am J Respir Crit Care Med

    (2002)
  • D.M. Black

    C-reactive protein and lipids may respond differently to statins

    Curr Atheroscler Rep

    (2003)
  • K.B. Bodman-Smith et al.

    C-reactive protein-mediated phagocytosis of Leishmania donovani promastigotes does not alter parasite survival or macrophage responses

    Parasite Immunol

    (2002)
  • C.E. Bolton et al.

    The CRP genotype, serum levels and lung function in men: the Caerphilly Prospective Study

    Clin Sci

    (2011)
  • M. Botto et al.

    Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

    Nat Genet

    (1998)
  • A. Brauweiler et al.

    Partially distinct molecular mechanisms mediate inhibitory FcgammaRIIB signaling in resting and activated B cells

    J Immunol

    (2001)
  • J.S. Brody et al.

    State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer

    Proc Am Thorac Soc

    (2006)
  • M. Bruijn et al.

    Association between C-reactive protein levels and outcome in acute lung injury in children

    Eur J Pediatr

    (2013)
  • D. Campa et al.

    Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer

    Carcinogenesis

    (2004)
  • C. Casals et al.

    Increase of C-reactive protein and decrease of surfactant protein A in surfactant after lung transplantation

    Am J Respir Crit Care Med

    (1998)
  • A.K. Chaturvedi et al.

    C-reactive protein and risk of lung cancer

    J Clin Oncol: Off J Am Soc Clin Oncol

    (2010)
  • D.P. Chew et al.

    Patterns of inflammatory activation associated with precipitants of acute coronary syndromes: a case-crossover study

    Intern Med J

    (2012)
  • K.S. Chew

    What's new in Emergencies Trauma and Shock? C-reactive protein as a potential clinical biomarker for influenza infection: more questions than answers

    J Emerg Trauma Shock

    (2012)
  • M. Chi et al.

    C-reactive protein induces signaling through Fc gamma RIIa on HL-60 granulocytes

    J Immunol

    (2002)
  • G.M. Corbo et al.

    C-reactive protein, lung hyperinflation and heart rate variability in chronic obstructive pulmonary disease – a pilot study

    COPD

    (2013)
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