J Physiol Biochem (2014) 70:263–270 DOI 10.1007/s13105-013-0297-9

MINI REVIEW

Nonmicrobial-mediated inflammatory airway diseases—an update Polani B. Ramesh Babu & P. Krishnamoorthy

Received: 11 July 2013 / Accepted: 17 October 2013 / Published online: 29 November 2013 # University of Navarra 2013

Abstract In lungs, airways are in constant contact with air, microbes, allergens, and environmental pollutants. The airway epithelium represents the first line of lung defense through different mechanisms, which facilitate clearance of inhaled pathogens and environmental particles while minimizing an inflammatory response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage through toll-like receptor, which acts as a gateway for all intracellular events leading to inflammation. In the absence of microbial stimulus, the immune system is capable of detecting a wide range of insults against the host. This review focuses on various molecular mechanisms involved in pathophysiology of airway inflammation mediated by environmental factors, cellular stress, and pharmacological and clinical agents. Keywords Nonmicrobial . Airways . Environmental agents . Immunity . Inflammation

Though exchange of gases (O2 and CO2) is the prime function of the lungs, it is a highly metabolically active organ in which blood, immune cells, and epithelial cells exhibit a strong interplay in maintaining homeostasis. To maintain host integrity, the innate immune system has evolved to sense not only microbial conserved

P. B. Ramesh Babu (*) : P. Krishnamoorthy Department of Bioinformatics, Bharath University, Selaiyur, Chennai, India e-mail: [email protected]

molecules in a pathogenic context but also sense many endogenous and exogenous nonmicrobial factors. The recently introduced “Danger Model” outlines that the immunity is more concerned with injury than with foreignness [40, 47]. If the immune system detects an infection, it also looks for signs of injury (broken cell parts, spilled cell constituents); in many cases, both an infection and an injury set off an inflammatory response. The initial processes following lung injury includes an acute inflammatory response, recruitment of immune cells, and epithelial cell spreading and migration [60, 69]. Recent findings suggested that toll-like receptors (TLRs) present in immune cells can respond to diverse nonmicrobial signals, which act as danger-associated molecular patterns (DAMPS) [34, 36, 73, 75]. At the site of inflammation, the interplay between pulmonary epithelium and immune cells results in production of pro- and anti-inflammatory mediators [6, 7, 79]. Inflammasome has recently been described as a multimolecular protein complex involved in activation of early inflammatory cascades (Fig. 1) [11, 12]. However, the nature of the physiological cues that trigger inflammasome activation remain incompletely understood. Many findings suggest that the inflammasome complex can be activated by host-derived danger signals such as monosodium urate crystals or extracellular ATP, bacterial or viral infection, as well as environmental stimuli including asbestos and UVB radiation [50, 55]. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, and cardiovascular and neurological diseases. Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible, and that is usually both progressive and

264 Fig. 1 Schematic model showing the initiation of inflammation by nonmicrobial stimuli. The activation of inflammasome by different nonmicrobial stimuli triggers the proteolytic cleavage of procaspase-1 into active caspase1, which, in turn converts pro-interleukin 1β (proIL1β) and pro-interleukin 18 (pro-IL18) into the mature IL1β and IL-18, respectively. The inflammasome complex consisted of nucleotidebinding domain leucine-rich repeat receptor (NLRP3), the adaptor protein ASC, and pro-caspases

P.B. Ramesh Babu, P. Krishnamoorthy

Non-microbial Stimuli (PAMPS and DAMPS)

NLRP-3 ASC

Nucleus

Inflammasome Complex

Pro-caspase1

Activated Caspase-1 Pro IL-1β β Pro IL-18

IL-1β β IL-18

Inflammation

associated with an abnormal inflammatory response of the lungs to noxious particles or gases. In COPD, hypoxia was shown to induce pulmonary inflammation by inducing activation of transcription factor hypoxiainducible factor-1 (HIF-1), which is a heterodimeric complex composed of an alpha and a beta subunit [29, 67]. The HIF-1a stimulates the expression of several genes encoding proteins that promote inflammatory reactions and this subunit is generally unstable and undergoes proteasomal degradation in normoxia, whereas the b subunit is permanently present in nuclei irrespective of the state of oxygenation [10, 28, 29, 51]. Both COPD and lung cancer are associated with cigarette smoking and/or various environmental pollutants exposure [35, 57, 80]. Inflammation is considered to initiate and promote lung cancer via the continuous formation of reactive oxygen or nitrogen species (ROS/RNS) that can bind to DNA, and thus lead to promutagenic DNA alterations [21, 80]. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumors [21, 46]. Asthma is a multifactorial airway disease triggered by the interaction of psychological stress with environmental agents. The basic premise of the model is that stress operates by altering the magnitude of the airway

inflammatory response that irritants, allergens (cat dander and mold), and infections bring about in persons with asthma. Environmental factors which appear to contribute to allergic sensitization in genetically predisposed individuals, include lower respiratory viral infections in early life and exposure to airborne environmental pollutants such as industrial air pollutants, diesel exhaust particulates, and traffic-related particulate pollutants [5, 23, 48, 58]. Acute lung injury (ALI) frequently occurs in traumatic patients and serves as an important component of systemic inflammatory response syndrome [45]. ALI and its more severe form acute respiratory distress syndrome (ARDS) are characterized by increased vascular and epithelial permeability, hypercoagulation and hypofibrinolysis, inflammation, and immune modulation [69]. These detrimental changes are orchestrated by cross-talk between a complex network of cells, mediators, and signaling pathways. Clinically, ARDS can be divided into ARDS due to direct causes such as pneumonia, aspiration or injurious ventilation, and due to extrapulmonary indirect causes such as sepsis, severe burns or pancreatitis. Pulmonary fibrosis, or interstitial lung disease, can be conceptualized as the pathological healing response to a spatially and temporally heterogeneous lung injury due to exogenous and endogenous factors [18, 72, 78, 84]. Idiopathic pulmonary fibrosis (IPF) is currently thought

Nonmicrobial-mediated inflammatory airway diseases—an update

to result from cell death primarily and inflammation secondarily [84]. The bleomycin-induced rodent model of lung fibrosis allows the use of molecular tools to dissect the cellular and subcellular processes leading to fibrosis. IPF occurs more frequently in males [17], cigarette smokers [8], and individuals that experience occupational exposure to metal or wood dust [2, 33]. Moreover, occupational exposure to asbestos can cause pulmonary fibrosis that is indistinguishable from IPF, and cytotoxic drugs and autoimmune conditions (e.g., collagen vascular diseases and inflammatory bowel diseases) can lead to other forms of idiopathic interstitial pneumonia [2]. In aggregate, the findings of Phillips et al. suggest that both exogenous and endogenous factors can provide the primary stimuli that lead to lung injury and focus the reparative process in the lung [59].

Environmental factors that trigger inflammation in airways Epidemiological and toxicological research suggests a causative relationship between various environmental agents and inflammation of lungs [4, 8, 24, 30, 33, 80]. Gene–environment interactions have also been identified as the indisputable cause of most respiratory diseases [8, 21, 24, 30, 45, 67, 80]. The airways have specialized mechanisms to protect alveoli from damages caused by toxic inhalation hazards which consist of noxious gases and vapors. Certain environmental irritants may activate various pattern recognition receptors on airway epithelial cells (AEC), generate reactive oxygen species, and upregulate antioxidant enzyme systems [4, 33, 34, 40, 43, 54] (Table 1). In parallel, intracellular signaling pathways are activated, triggering production of cytokines that can recruit and stimulate innate immune helper cells (dendritic and Th2 cells) resulting in allergic inflammatory response [24, 39, 53]. The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to oxidizing, electrophilic, acidic, or basic gases frequently occur in occupational and ambient environments. Experimental evidence suggests that complex organic molecules from diesel exhaust may act as allergic adjuvants through the production of oxidative stress in airway cells [5, 23, 54]. Cigarette smoke can release CXCL-8 and IL-1β mediators in AECs, which are involved in acute and chronic

265

inflammatory processes in COPD [54, 80], which in turn increase the risk for developing lung cancer. Ambient ozone is another potential air pollutant that causes lung toxicity and modifies genes of innate immunity [27]. Anthracofibrosis is described as a bronchial stenosis caused due to exposure of smoke from biofuel or biomass combustion, coal miners, and mineral dusts [25]. In newly employed coal miners, bronchitic symptoms are reportedly associated with a rapid decline in lung function within 2 years after starting work [68]. Cumulative exposure to coal dust is a significant risk factor for the development of emphysema and has an additive effect to smoking with increased risk of death from COPD. Inhalant exposure of silica has been linked to the development of pulmonary fibrosis by triggering IL1β release from macrophages in an inflammasomedependent manner [12, 19, 31, 44]. Sulfur mustard (SM) is an organic gas highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and ARDS. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lungs after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier [77]. Phosgene is a substance of immense importance in the chemical industry whose exposure induces acute lung injury; because of its widespread industrial use, there is potential for small-scale exposures within the workplace, large-scale accidental release, or even deliberate release into a built-up area. The mechanisms underlying the phosgene-induced acute lung injury are not well understood [26]. Lung injuries caused by microparticles and chlorine gas were reported by a few investigators [32, 49, 81]. Swine barn air was described as an occupational hazard and barn workers following an 8-h work shift were reported to develop many signs of lung dysfunction including lung inflammation [38]. In recent decades, advances in nanotechnology engineering have given rise to the rapid development of many novel applications in the biomedical field. Nanoparticles (NPs) with a more reactive surface may undoubtedly generate inflammation more readily, which could be sufficiently intense to lead to secondary

266

P.B. Ramesh Babu, P. Krishnamoorthy

Table 1 Environmental agents causing airway inflammation Stimulus

Disease/impact on airways

Mechanism/cellular target reported

References

Diesel exhaust

Pattern recognition receptors, chemokines, cytokines, mucosal layer Pattern recognition receptor, CXCL-8, IL-1 β

[5, 23, 54]

Cigarette smoke

Airway damage, oxidative stress, asthma Cancer, COPD

[8, 24, 80]

Ozone

Lung toxicity

Genes of innate immunity

[27]

Biofuel or biomass combustion Coal dusts

Mucosal layer

[25]

Airway obstruction, oxidative stress

[25, 68]

Silica

Anthracofibrosis (bronchial stenosis) Fibrosis, emphysema pneumoconiosis Pulmonary fibrosis

Sulfur mustard

ARDS, obstructive disease

IL-1 beta, inflammasome

[12, 19, 31, 44] [77] [26] [32, 49, 81]

Phosgene

Acute lung injury

↑ MMPs ,TNFα, ROS and other proinflammatory mediators. Disruption of epithelial barrier Mechanism unknown

Microparticles and chlorine gas Swine barn air

Lung injury

↑ Vascular and epithelial permeability

Nanoparticles

Lung inflammation

Monocyte and macrophage recruitment

[38]

Cancer, fibrosis, and pneumoconiosis

Nanoparticle-associated molecular patterns (NAMPS), oxidative stress, and DNA damage

[42, 44, 70]

carcinogenesis via the oxidants and mitogens produced during inflammation. In the workplace environment, the lungs are one of the main routes of entry for NPs into the body and, hence, a likely site for accumulation of NPs. Once NPs enter the air spaces and are quickly taken up by alveolar cells, they are likely to induce toxic effects such as generation of oxidative stress, DNA damage, and inflammation leading to fibrosis and pneumoconiosis. All these examples could lead to new area of research to evaluate interaction of NPs with the immune system and whether they should be considered as danger signals capable of becoming NAMPS (nanoparticle-associated molecular patterns) that act as a newly identified “alarmin” [42, 44, 70].

Cellular metabolites and stress-related airway inflammation The continuous physiological process of gaseous exchange through contraction and relaxation and mucociliary clearance of microbes and nonmicrobial particles keep lungs metabolically active. However, beyond the limit of homeostasis, the AECs undergo metabolic or cellular stress resulting in stimulation of inflammatory cascade through cellular metabolites (Table 2). In healthy airways, ATP released from cells

is tightly regulated and its concentration is kept low by extracellular ATP/ADPases [56, 66] and adenosine is known to regulate mucociliary clearance in airway epithelia [41, 76]. Patients with chronic lung pathology such as allergic asthma or COPD were reported to present enhanced ATP levels in the bronchoalveolar space [66]. In damaged tissues, massive ATP escape from cells results in high local concentration of extracellular ATP (eATP) which acts as natural endogenous adjuvant that initiates inflammation through danger signal through P2X7 receptor/pannexin-1 axis leading to lung IL-1β maturation [41, 56, 76]. Uric acid is another metabolite released from damaged cells and serves as a danger signal that alerts the immune system to potential threats, even in the absence of microbial infection [16, 65]. The increased oxidative stress in patients with COPD is the result of a large burden of inhaled oxidants, as well as increased amounts of ROS generated by various inflammatory, immune, and epithelial cells of the airways [4, 69, 80]. These include oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, mitochondrial respiration, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. Two recent studies have provided evidence that mitochondria are the principal source of ROS required for inflammasome activation [71, 83].

Nonmicrobial-mediated inflammatory airway diseases—an update

267

Table 2 Cellular metabolites and airway Inflammation Stimulus

Disease/impact on airways

Mechanism/cellular target reported

References

Cellular ATP

Allergy, inflammation

[56, 65, 66]

Adenosine

Inflammation

Uric Acid

Inflammation

P2X7 receptor/pannexine-1, IL-1 β maturation and mucociliary clearance Mucociliary clearance and cell volume regulation Inflammasome activation

Reactive oxygen species Endoplasmic reticulum

Oxidative stress, epithelial injury, and COPD Cellular and metabolic stress

Hypotonicity

Inflammation

At the intracellular level, the endoplasmic reticulum (ER) is responsible for much of a cell’s protein synthesis and folding, but it also has an important role in sensing cellular stress [64, 82]. New observations suggest that a form of ER stress, the unfolded protein response (UPR) is activated in airway epithelia by bacterial infectioninduced airway inflammation. UPR-dependent signaling is responsible for the ER Ca (2+) store expansion-mediated amplification of airway inflammatory responses [63]. Hypotonicity could be another “danger signal”, the mechanism by which it triggers IL-1β release, and thereby inflammation, has long remained obscure. The most interesting novel observation is that hypotonicity-associated K+ efflux is a necessary, but not sufficient, event to switch on the inflammasome [15, 52]. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation in airways.

[41, 76] [16, 65]

Inflammasome activation

[4, 69, 71, 80, 83]

UPR-dependent signaling and Ca2+ IL1- β, K+ efflux, Inflammasome

[63, 64, 82] [15, 52]

Pharmacological or clinical impacts on airway inflammation Patients in critical conditions are supported with oxygen through mechanical ventilation, which can cause profound molecular and cell-mediated changes in airways by several mechanisms such as free radicalinduced cellular damages, increased endothelial and epithelial permeability, decreased cellular proliferation, inflammation, and necrosis [13, 37, 76] (Table 3). In ventilator-induced lung injury (VILI), the cyclic closure and reopening of pulmonary airways at low lung volumes, i.e., derecruitment and recruitment, also causes significant lung damage and inflammation. Scientific evidence supports a link between VILI and the development of extrapulmonary organ dysfunction, similar to how most severe cases of sepsis are clinically manifested [14, 74]. Under hyperoxic conditions, the mechanisms of oxygen toxicity are incompletely

Table 3 Pharmacological or clinical impacts on airway inflammation Stimulus

Disease/impact on airways

Mechanism/cellular target reported

References

Mechanical ventilator

Lung damage/inflammation

↑ Endothelial/epithelial permeability ↓ Cellular proliferation Free radicals, cytokine mediators

[13, 14, 37, 74]

↑ Oxidant-induced inflammation ↓ Glutathione T-helper type 2 responses Fibroblast proliferation and extracellular matrix

[1, 9]

Hyperoxia

Inflammation/necrosis

Paracetamol

Asthma, rhinoconjunctivitis

Bleomycin, busulfan, and gefitinib

Acute alveolitis and interstitial inflammation

[14, 74]

[3, 20, 22, 66, 72]

268

understood. Recently, in vitro models were developed using airway epithelial cells to study the mechanisms of airway protein secretions under hyperoxia injuries [61, 62]. Barotrauma is another type of ventilator-induced lung injury caused by high airway pressures, which is associated with the development and persistence of alveolar and airway structural damage, pulmonary edema, and is also implicated in the incitement of an inflammatory response, which may become chronic. The use of paracetamol (acetaminophen) in infancy or childhood and the subsequent development of asthma were previously well documented by several authors [1, 9]. The mechanism of pharmacalogical agents such as bleomycin, busulfan, and gefitinib inducing lung injury is poorly understood. Bleomycin is a chemotherapeutic drug used clinically for a variety of human malignancies, including lymphoma. In human patients and rodent model, bleomycin treatment resulted in acute alveolitis and interstitial inflammation, characterized by recruitment of neutrophils, lymphocytes, and macrophages in the acute phase [20]. Subsequently, fibrotic responses occur, characterized by an increase in fibroblast proliferation and extracellular matrix synthesis. Previous studies suggested various mediators (i.e., cytokines and chemokines, including TNF-α, transforming growth factor-b, IL-1b, macrophageinflammatory protein-1a, monocyte chemoattractant protein-1, ROS, and Fas/Fas ligand) interactions mediate bleomycin-induced pulmonary inflammation and fibrosis in mice [3, 22, 66, 72]. Inflammation of nonmicrobial origin involves multiple cell types of immune cells and airway epithelium. Certain other nonmicrobial signals involve noxious physical or chemical stimuli of external origin or internal stimuli of other pathophysiological conditions such as tumor microenvironment, respiratory–gastrointestinal cross-talk, fluid imbalance of cystic fibrosis airways, psychological stress, autoimmune and auto-inflammatory syndromes, etc. The TLRs and molecular pattern recognition receptors appear to play a key role in immune inflammatory pathways. Some of the NOD-like receptors (NLRs) are recently reported to sense nonmicrobial danger signal, which results in production of proinflammatory cytokines. The regulatory mechanisms of nonmicrobial (sterile)-mediated inflammation through TLRs, DAMPS, PAMPS, NLRs, and airway sensory receptors leads to richer understanding of immune inflammatory pathways, which opens new opportunities for

P.B. Ramesh Babu, P. Krishnamoorthy

pharmacological therapeutic interventions in a variety of airway inflammatory disorders. Acknowledgments The authors thank the management, faculties and staffs of Bharath University, Chennai, India for their support and encouragement.

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