CC and CXC Chemokines Induce Airway Smooth Muscle Proliferation and Survival

Abstract

The increase in airway smooth muscle (ASM) mass is a major structural change in asthma. This increase has been attributed to ASM cell (ASMC) hyperplasia and hypertrophy. The distance between ASMC and the epithelium is reduced, suggesting migration of smooth muscle cells toward the epithelium. Recent studies have suggested a role of chemokines in ASMC migration toward the epithelium; however, chemokines have other biological effects. The objective of the current study is to test the hypothesis that chemokines (eotaxin, RANTES, IL-8, and MIP-1α) can directly influence ASMC mass by increasing the rate of proliferation or enhancing the survival of these cells. Human ASMCs were exposed to different concentrations of eotaxin, RANTES, IL-8, or MIP-1α. To test for proliferation, matched control and stimulated ASMC were pulsed with [3H]thymidine, or ASMCs were stained with BrdU and then analyzed with flow cytometry. Apoptosis was measured using Annexin V staining and flow cytometry. Expression of phosphorylated p42/p44 and MAPKs was assessed by Western blot. In a concentration-dependent manner, chemokines including eotaxin, RANTES, IL-8, and MIP-1α increased ASMC’s [3H]thymidine incorporation and DNA synthesis. IL-8, eotaxin, and MIP-1α decreased the rate of apoptosis of ASMCs compared with the matched controls. A significant increase in phosphorylated p42/p44 MAPKs was seen after treating ASMCs with RANTES and eotaxin. Moreover, inhibition of p42/p44 MAPK phosphorylation reduced the level of chemokine-induced ASM proliferation. We conclude that chemokines might contribute to airway remodeling seen in asthma by enhancing the number and survival of ASMCs.

YKL-40 Induces IL-8 Expression from Bronchial Epithelium via MAPK (JNK and ERK) and NF-κB Pathways, Causing Bronchial Smooth Muscle Proliferation and Migration

“…IL-8 has been reported to trigger calcium release, contraction, and migration in BSMCs (47-49) through its functional receptors (50, 51). Halwani et al (52) reported that chemokines (including IL-8) may contribute to airway remodeling of asthma by enhancing the number and survival of BSMCs. However, the role of IL-8 on YKL-40-related remodeling of asthma remains unknown.…”

Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

“…CCR1, when stimulated by its ligand CCL5, regulated ASM cell proliferation via p42/p44 MAPK activation (55). Similarly, CCR3, when stimulated by its ligand CCL11/eotaxin, regulated ASM cell migration and proliferation via p42/p44 MAPK activation (55,70,136). The CCR7-CCL19 interaction increased ASM cell migration (73).…”

“…Both CC and CXC chemokine receptors have also been found expressed in ASM cells, where they have been involved mainly in migration and proliferation processes. CCR1, when stimulated by its ligand CCL5, regulated ASM cell proliferation via p42/p44 MAPK activation (55). Similarly, CCR3, when stimulated by its ligand CCL11/eotaxin, regulated ASM cell migration and proliferation via p42/p44 MAPK activation (55,70,136).…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…Here, in contrast to the substantial data on increased ASM cell proliferation, there is much less information on apoptosis per se. Some studies have reported reduced rates of ASM apoptosis following exposure to Th17-associated cytokines (39), IL-8, eotaxin, and monocyte inflammatory protein-1a (107), as well as with TRPV1 agonist (354), extracellular laminin (313), and ␥-glutamyl transpeptidase-1 (GGT1) antagonism (83). However, several other studies have found that mechanisms such as phosphatase and tensin homolog deleted on chromosome 10 (182), PPAR-␥ (73), collagens (274), and vitamin D (50) modulate ASM cell proliferation but do not influence apoptosis.…”