TIME COURSE OF PULMONARY RESPONSE OF RATS TO INHALATION OF CRYSTALLINE SILICA: NF-kappa B ACTIVATION, INFLAMMATION, CYTOKINE PRODUCTION, AND DAMAGE

Abstract

In vitro studies suggest that silica-induced lung disease may be linked to processes regulated by nuclear factor-kappa B (NF-kappa B) activation, but this has not been examined in vivo. Rats were exposed to a silica aerosol of 15 mg/m(3) (6 h/day, 5 days/wk) for 116 days, and bronchoalveolar lavage (BAL) was conducted at various times during the exposure. Silica-induced pulmonary inflammation and damage were determined by measuring BAL cell differentials and first BAL fluid lactate dehydrogenase (LDH) activity and serum albumin concentrations, respectively. NF-kappa B activation and production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) by BAL cells were also measured. The results demonstrate that NF-kappa B activation occurred after 5 days exposure, and continued to increase thereafter. BAL cell production of IL-1 and TNF-alpha had increased incrementally by 10 and 30 days of exposure, respectively. This elevation continued through 79 days of exposure before further increasing at 116 days of exposure. Pulmonary inflammation and damage in silica-exposed rats were also significantly elevated at 5 days of exposure, further increased at a slow rate through 41 days of exposure, and dramatically increased thereafter. Taken together, the results indicate that the initial molecular response of NF-kappa B activation in BAL cells occurs in response to low levels of silica deposition in the lung and increases more rapidly versus exposure duration than silica-induced pulmonary inflammation, cellular damage, and cytokine production by BAL cells. This suggests that NF-kappa B activation in BAL cells may play an important role in the initiation and progression of silica-induced pulmonary inflammation, cellular damage, and fibrosis.

Silica Induces Macrophage Cytokines through Phosphatidylcholine-Specific Phospholipase C with Hydrogen Peroxide

“…Cytokine induction after silica particle exposure in alveolar macrophages has been well established (6). PC-PLC has been reported to be involved in NF-B activation and cytokine production (16,17).…”

“…The silica-associated inflammatory response is triggered by cytokines released from alveolar macrophages. For example, TNF-␣ (2, 3)and IL-1␤ (4,5), two cytokines that play important roles in the inflammatory response, are increased after silica particle exposure in alveolar macrophages (6). These inflammatory cytokines can in turn recruit more inflammatory cells into the alveolus and propagate the inflammatory response and injuries (7).…”

Subcutaneous administration of infliximab-attenuated silica-induced lung fibrosis

“…Nuclear factor-κB as a transcription factor plays a fundamental role in the pathogenesis of silicosis. Binding of NF-κB to DNA promotes up-regulation of inducible genes involved in mediating the inflammatory and fibrotic responses to silica [14][15][16]. Tumor necrosis factor α also activates inducible nitric oxide synthase (iNOS) to produce nitric oxide (NO) in respiratory epithelium [17].…”

“…Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1, neutralizing TNF-α biologic activity with a high affinity and specificity to human membrane-bound and soluble TNF-α [20][21][22]. Infliximab has demonstrated a protective effect on acute lung injury induced by intestinal isch-IJOMEH 2018;31(4) 505 average score was calculated for each group [15]. The Masson's trichrome staining method was used for determining the severity of fibrosis and the quantitative grade of pulmonary fibrosis was blindly scored by randomly selecting regions according to the method introduced by Ortiz et al [16].…”

Does the Harvard/U.S. Environmental Protection Agency Ambient Particle Concentrator Change the Toxic Potential of Particles?

“…28 Numerous animal studies confirm the pro-inflammatory capabilities of crystalline SiO 2 . 29,30 Crystalline silicas are of variable toxicity because of physical properties and structure. 27,31,32 These factors are important in the stimulation of macrophages to produce inflammatory and fibroproliferative factors.…”