Role of CXCL5 in Leukocyte Recruitment to the Lungs during Secondhand Smoke Exposure

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States. The major cause of COPD is cigarette smoking. Extensive leukocyte influx into the lungs, mediated by chemokines, is a critical event leading to COPD. Although both resident and myeloid cells secrete chemokines in response to inflammatory stimuli, little is known about the role of epithelial-derived chemokines, such as CXC chemokine ligand (CXCL)5, in the pathogenesis of cigarette smoke-induced inflammation. To explore the role of CXCL5, we generated CXCL5 genedeficient mice and exposed them to secondhand smoke (SHS) for 5 hours/day for 5 days/week up to 3 weeks (subacute exposure). We observed a reduced recruitment of leukocytes to the lungs of CXCL5 2/2 mice compared with their wild-type (WT) counterparts, and noted that macrophages comprised the predominant leukocytes recruited to the lungs. Irradiation experiments performed on CXCL5 2/2 or WT mice transplanted with WT or CXCL5 2/2 bone marrow revealed that resident but not hematopoietic cell-driven CXCL5 is important for mediating SHS-induced lung inflammation. Interestingly, we observed a significant reduction of monocyte chemotactic protein-1 (MCP-1/CC chemokine ligand 2) concentrations in the lungs of CXCL5 2/2 mice. The instillation of recombinant MCP-1 in CXCL52/2 mice reversed macrophage recruitment. Our results also show the reduced activation of NF-kB/p65 in the lungs, as well as the attenuated activation of C-Jun N-terminal kinase, p42/44, and p38 mitogen-activated protein kinases and the expression of intercellular adhesion molecule-1 in the lungs of SHS-exposed CXCL5 2/2 mice. Our findings suggest an important role for CXCL5 in augmenting leukocyte recruitment in SHS-induced lung inflammation, and provide novel insights into CXCL5-driven pathogenesis.Keywords: smoke; CXCL5/LIX; macrophages; chemokines; cytokines Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States (1-3). According to recent reports, the prevalence of COPD in the United States involves more than 12 million, with an annual mortality of 120,000 (1-3). COPD is an irreversible disease characterized by airway inflammation (chronic bronchitis) and airspace enlargement, along with the destruction of lung parenchyma (emphysema) (4, 5). Although the molecular and cellular mechanisms that contribute to the development of COPD are not well understood, substantial recruitment and activation of inflammatory cells into the airspaces and lung parenchyma has been documented in humans with COPD and implicated in its pathogenesis (4, 5).Cigarette smoking accounts for most of the debilitating effects of COPD, but other environmental risk factors include air pollution and chronic occupational exposure to various dusts (6). Why only a small proportion (10-20%) of smokers develops COPD remains unclear (7). Cigarette smoke (CS) contains more than 4,700 chemicals (8), and is a powerful inducer of inflammatory mediators, including oxidants and proteases,...

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Diverse macrophage populations mediate acute lung inflammation and resolution

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