Inflammation has been known to mankind since ancient times; the first description of inflammation came from Aulus Cornelius Celsus, a Roman encyclopedist in the first century, who documented four cardinal signs of inflammation: rubor, calor, dolor, and tumor (redness, heat, pain, and swelling). Inflammation is basically a host defense response to tissue injury occurring from infection, wounding, or chemical exposure, causing redness, heat, pain, and swelling in the affected area. It serves to orchestrate a multifactorial network of chemical signals to remove the invading microbial pathogen and facilitate the healing of the injured tissue. Inflammation is usually self-limiting, but in many disease states it becomes exuberant and persistent, causing detrimental effects and further injury to the host tissues (). Therefore, the efficacy of treating inflammation-associated diseases may lie in strategies aimed at dampening inflammation rather than abolishing it (). The development of such a therapeutic strategy depends on uncovering the intricate signaling network in control of the initiation, maintenance, and resolution phase of inflammation, which may lead to identification of suitable targets whose inhibition selectively suppresses the detrimental inflammation without compromising the host defense response.
Figure 1. (A) Inflammation is usually self-limiting; it is activated in response to injury or infection and resolves with elimination of the invading pathogen or healing of the injured tissue. However, in many disease conditions, inflammation becomes excessive, (more ...)
A characteristic feature of pulmonary inflammation is the massive infiltration of leukocytes, particularly neutrophils (i.e., polymorphonuclear leukocytes [PMNs]) in the lung that ultimately leads to disruption of capillary–alveolar barriers and the development of pulmonary edema with severe consequences for pulmonary gas exchange (1
). To reach an inflammatory site in the pulmonary tissues and alveolar spaces, circulating PMNs must first traverse the endothelial barrier (the inner lining of blood vessel), a process referred to as diapedesis or transendothelial migration (TEM). TEM of PMNs is mediated by a cascade of cellular events initiated by infectious agents or noninfectious inflammatory stimuli. The sequence of events is initiated with local activation of rapidly responding resident cells, primarily macrophages, in the lung interstitium and alveolus, resulting in the release of several proinflammatory cytokines, including tumor necrosis factor (TNF)-α, IL-1β, and chemokines such as IL-8 and macrophage inflammatory protein 2-α (3
). These soluble mediators serve to establish autocrine and paracrine loops to further activate the macrophages and endothelial cells (ECs). Activated endothelium produces numerous molecules, including adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1 [ICAM-1]), cytokines (TNF-α, IL-1β, IL-6), and chemokines (IL-8/CXCL8). The coordinate action of these proteins promotes lung PMN recruitment by facilitating adhesion and TEM of PMNs (5
). An essential event mediating the expression of genes encoding cytokines, chemokines, and adhesion molecules involves activation of the transcription factor nuclear factor kappa B (NF-κB) (4