Inflammatory signalings involved in airway and pulmonary diseases

Abstract

In respiratory diseases, there is an increased expression of multiple inflammatory proteins in the respiratory tract, including cytokines, chemokines, and adhesion molecules. Chemokines have been shown to regulate inflammation and immune cell differentiation. Moreover, many of the known inflammatory target proteins, such as matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and cytosolic phospholipase A2 (cPLA2), are associated with airway and lung inflammation in response to various stimuli. Injuriously environmental stimuli can access the lung through either the airways or the pulmonary and systemic circulations. The time course and intensity of responses by resident and circulating cells may be regulated by various inflammatory signalings, including Src family kinases (SFKs), protein kinase C (PKC), growth factor tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS), PI3K/Akt, MAPKs, nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), and other signaling molecules. These signaling molecules regulate both key inflammatory signaling transduction pathways and target proteins involved in airway and lung inflammation. Here, we discuss the mechanisms involved in the expression of inflammatory target proteins associated with the respiratory diseases. Knowledge of the mechanisms of inflammation regulation could lead to the pharmacological manipulation of anti-inflammatory drugs in the respiratory diseases.

Figure 1

General overview of the inflammatory target proteins in respiratory diseases. Many of the known inflammatory target proteins, such as MMP-9, ICAM-1, VCAM-1, COX-2, and cPLA₂, are induced by various stimuli, such as mitogens, growth factors, virus infection, cytokines, and bacterial infection. EGF, epidermal growth factor; PDGF, platelet derived growth factor; EV71, enterovirus 71; JEV, Japanese encephalitis virus; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; LPS, lipopolysaccharide; LTA, lipoteichoic acid.

Figure 2

The signaling pathways in airway and pulmonary inflammation. Various stimuli, such as mitogens, growth factors, virus infection, cytokines, and bacterial infection, can induce inflammation via the NADPH oxidase/ROS, PKCs, c-Src, EGFR, PDGFR, PI3K/Akt, and MAPKs pathways and the transcription factors, such as NF-κB and AP-1 in lung resident cells.

Figure 3

General overview of the inflammatory signaling pathways in respiratory diseases. Many of the known inflammatory target proteins, such as MMP-9, ICAM-1, VCAM-1, COX-2, and cPLA₂, are associated with inflammatory signaling pathways induced by various stimuli, including TNF-α, IL-1β, ATP, cigarette smoke, LTA, or LPS. Moreover, the SFKs, PKCs, growth factor tyrosine kinase receptors, NADPH oxidase/ROS, PI3K/Akt, and MAPKs are components of signaling cascades that respond to extracellular stimuli by targeting transcription factors, such as NF-κB and AP-1, resulting in the modulation of inflammatory gene expression associated with pulmonary diseases.