Signal Transduction Pathways Linking the Activation of Alveolar Macrophages With the Recruitment of Neutrophils to Lungs in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem. It is predicted by the World Health Organization to become the third most common cause of death and the fifth most common cause of disability in the world by 2020. COPD is a complex inflammatory disease involving several types of inflammatory cells and multiple inflammatory mediators. Although abnormal numbers of inflammatory cells such as macrophages, dendritic cells, neutrophils, and T lymphocytes have been documented in COPD, the relationship between these cell types and the sequence of their appearance and persistence is largely unknown. Alveolar macrophages have been identified as one of the major cell types that plays a key role in orchestrating the inflammatory events associated with the pathophysiology of COPD. One of the major functions of macrophages is the secretion of chemotactic factors and this function is markedly increased on exposure to cigarette smoke (CS). This enhanced release of chemoattractants results in increased lung neutrophil infiltration, which is thought to be a key event in the development of COPD. The molecular basis for this amplified inflammatory response is not very clear, but it could be due to an alteration in signal transduction pathways within the macrophage. Based on existing literature, an attempt has been made to create a comprehensive review of the signal transduction pathways that link the activation of macrophages with the increased recruitment of neutrophils into the airways. Some of the major stimuli that activate macrophages and cause them to secrete chemotactic factors have been identified as CS, wood smoke, ozone, bacterial endotoxin, and proinflammatory cytokines such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. These stimuli seem to activate mainly redox-sensitive transcription factors such as nuclear factor (NF)-kappa B and activator protein (AP)-1, both of which play a major role in the synthesis and secretion of chemotactic factors such as IL-8 and leukotriene B(4) (LTB(4)). The pathways involved in the synthesis and secretion of other factors such as macrophage chemotactic protein-1 (MCP-1) and growth-related oncogene-alpha (Gro-alpha) have also been reviewed.

Azithromycin inhibits macrophage interleukin-1β production through inhibition of activator protein-1 in lipopolysaccharide-induced murine pulmonary neutrophilia

“…Since the promoter region in the IL-1β gene contains binding motifs for AP-1 [35,36] inhibition of its activation will result in reduced IL-1β production. Having in mind that several studies have identified IL-1β as one of the major cytokines driving neutrophil accumulation in lung tissue [26][27][28][29]39,40], inhibition of AP-1 activation and consequent IL-1β production by alveolar macrophages seems to be a sufficient and likely mechanism by which azithromycin reduced neutrophil accumulation in the lungs following LPS challenge (concept summarized in Fig. 9).…”

Bovine Endometrial Stromal Cells Support Tumor Necrosis Factor Alpha-Induced Bovine Herpesvirus Type 4 Enhanced Replication1

“…Generally, bacteria and viruses that survive host defense mechanisms and proliferate within the animal body are the main triggering factors of inflammation and PMNs are directly and indirectly responsible for most of the observed pathological changes and lesions [36,37]. Mobilization of PMNs in the inflamed tissue is modulated by interactions among leucocytes and cytokines.…”

“…Mobilization of PMNs in the inflamed tissue is modulated by interactions among leucocytes and cytokines. During the acute-phase response of the inflammatory process caused by infectious agents in ruminants and humans, inflammatory cytokines such as interleukin (IL)-1b, TNF-a, and IL-8, secreted by a variety of immune and nonimmune cell types, induce intense PMN mobilization and an increased inflammatory response [36,37]. PMN mobilization does not always effectively combat the infection and may also contribute to the development of lesions.…”

The Biochemistry of Endothelial Cells

“…Initially recruited neutrophils undergo apoptosis and alveolar macrophages engulf these cells, a process that results in the production of active TGFb (Fadok et al, 1998). A number of key molecules have been identified in the process of inflammatory cell recruitment and include selectins, integrins, cytokines, and growth factors, the innate immune system including TLRs, surfactant protein A (SPA) and SPD, as well as components of the extracellular matrix (Reidy and Wright, 2003;Reutershan and Ley, 2004;Craig et al, 2009;Murugan and Peck, 2009).…”