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==Overview==
==Overview==
== Pathogenesis ==
Occupational lung diseases include the pneumoconioses (interstitial lung diseases), hypersensitivity pneumonitis, bronchiolitis, byssinosis, and occupational asthma. Pneumoconiosis is an [[interstitial lung disease]] caused by the accumulation of different dust particles in the alveolar space. As the particles accumulate, the body's elimination mechanisms begin to fail, resulting in activation of chemotactic factors that exacerbate the inflammatory response, and subsequently lead to [[fibrosis]]. Hypersensitivity pneumonitis, bronchiolitis, bysinnosis and occupational asthma are all part of the respiratory systems’ over reactivity to inhalants.  
Coal dust that enters the lungs can neither be destroyed nor removed by the body. The particles are engulfed by resident alveolar or interstitial [[macrophage]]s and remain in the lungs, residing in the connective tissue or pulmonary [[lymph node]]s. Aggregations of carbon-laden macrophages can be visualized under a microscope as granular, black areas. In serious cases, the lung may grossly appear black. These aggregations can cause inflammation and fibrosis, as well as the formation of nodular legions within the lungs. The centres of dense legions may become necrotic due to [[ischaemia]], leading to large cavities within the lung.


== Appearance ==
==Pathophysiology==
Simple CWP is marked by the presence of 1-2mm nodular aggregations of anthracotic macrophages, supported by a fine collagen network,  within the lungs. Those 1-2mm in diameter are known as ''coal macules'', with larger aggregations known as ''coal nodules''. These structures occur most frequently around the initial site of coal dust accumulation - the upper regions of the lungs around [[respiratory bronchiole]]s<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| location=Philadelphia| id=0-7216-7335-X}}</ref>.


Continued exposure to coal dust following the development of simple CWP may result in its progression to complicated CWP, which generally requires a number of years to develop. Large, black, fibrotic scars 2-10cm in diameter are present, with accompanying decreased lung function. The lung itself appears blackened. A minority of these cases progresses to [[progressive massive fibrosis]] (PMF), the most serious form of CWP.
===Pathogenesis===




Anthracosis is the asymptomatic accumulation of carbon without a consequent cellular reaction. Such accumulation can be found in varying degrees among most urban dwellers and in tobacco smokers. Inhaled coal dust becomes a problem when the body's natural mechanisms for defending against and processing the dust becomes overwhelmed and, subsequently, overreactive.
==Pathophysiology==
The pathogenesis of pneumoconiosis starts with the inhalation of mineral, metallic or dust particles. . <ref name="pmid10931786">{{cite journal| author=Castranova V, Vallyathan V| title=Silicosis and coal workers' pneumoconiosis. | journal=Environ Health Perspect | year= 2000 | volume= 108 Suppl 4 | issue=  | pages= 675-84 | pmid=10931786 | doi= | pmc=PMC1637684 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10931786  }} </ref><ref name="pmid10931786">{{cite journal| author=Castranova V, Vallyathan V| title=Silicosis and coal workers' pneumoconiosis. | journal=Environ Health Perspect | year= 2000 | volume= 108 Suppl 4 | issue=  | pages= 675-84 | pmid=10931786 | doi= | pmc=PMC1637684 |vurl=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10931786  }} </ref>. <ref> name="pmid9072984">{{cite journal| author=Boitelle A, Gosset P, Copin MC, Vanhee D, Marquette CH, Wallaert B et al.| title=MCP-1 secretion in lung from nonsmoking patients with coal worker's pneumoconiosis. | journal=Eur Respir J | year= 1997 | volume= 10 | issue= 3 | pages= 557-62 | pmid=9072984 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9072984  }} </ref> unclear <ref name="pmid7656959">{{cite journal| author=Vanhée D, Gosset P, Boitelle A, Wallaert B, Tonnel AB| title=Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis. | journal=Eur Respir J | year= 1995 | volume= 8 | issue= 5 | pages= 834-42 | pmid=7656959 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7656959  }} </ref>


Inhaled coal dust reaches the terminal bronchioles, and the carbon is engulfed by alveolar and interstitial macrophages. Phagocytosed coal particles are transported by macrophages up the mucociliary elevator and are expelled in the mucus or through the lymphatic system.
The most common particles that cause pneumoconiosis are:
*[[Asbestos]]
*[[Silica]] (quartz, cristobalite, coesite or tridymite silica polymorphs)
**Structural differences between the polymorphs of silica, are important because of the different degrees of biological reactivity they present, making some of them more toxic than others. The biological reactivity makes quartz more toxic, followed by tridymite, cristobalite, coesite, and finally stishovite.  


When this system becomes overwhelmed, the dust-laden macrophages accumulate in the alveoli and may trigger an immune response. (The lungs must be exposed for a significant amount of time to dust particles 2-5 µm in diameter in order for the dust to be retained in the alveoli.) Fibroblasts involved in this response secrete reticulin, which entraps the macrophages. If the macrophages lyse, the fibroblastic response is augmented and more reticulin is laid down in the area.
*[[Coal]]


Coal that contains silica lyses macrophages faster and stimulates the fibroblasts to add more collagen to the network. The lymphatic tree is contained in the pulmonary interstitium, along with arterial and venous vessels. If these macrophages have partially migrated up the lymphatic vessels, arterioles can become strangulated from the resultant interstitial fibrosis. As more and more dying macrophages, fibroblasts, reticulin, and collagen are deposited along the vascular tree, the vessels become compromised, and ischemic necrosis ensues.
*Other dust particles may also lead to pneumoconiosis, such as hydrated magnesium silicate, hydrous aluminum silicate, bauxite, cobalt, beryllium and iron.


Areas of focal deposition of coal dust and pigment-laden macrophages are known as coal macules and are the histologic hallmark of coal worker’s pneumoconiosis. As these macules extend, they join other macules in the vicinity, forming discrete areas of interstitial fibrosis. This growing collagen network causes distention of the respiratory bronchioles, forming focal areas of emphysema. Widespread areas of focal emphysema can accrue without significant respiratory impairment.
===Biological Reactivity of Different Dust Particles===
Each dust particle has a different degree of biological reactivity. This variability is due to properties in the surface of the particles. In the case of silica, there are two theories explaining their biological reactivity. One of them is that silica is a hydrogen donor, whereas biological macromolecules are hydrogen acceptors, creating strong hydrogen bonds that contribute to the damage. The other theory is that at a pH of 7.0, silica is negatively charged, and therefore attracting alveolar macrophages, and activating the generation of reactive oxygen species and cytokines.


A study of autopsied coal miners and non-miners conducted by Kuempel et al showed that inhalation of respirable coal dust is a highly significant predictor of emphysema severity beyond other contributory factors, including cigarette smoking, race, and age at death. [3, 4]
Shown below is a table summarizing the dust exposure associated with pneumocociosis.


Depending on factors that are still not fully understood, the macules may arrest or may continue to enlarge and form nodules that produce progressive massive fibrosis when they coalesce. This process can be exacerbated by tuberculosis or rheumatoid factor, which accelerates the rate of progression of focal ischemic necrosis and fibrosis.
{| class="Dust Exposure Associated with Pneumoconiosis" border="1"


Progressive massive fibrosis in association with rheumatoid arthritis is known as Caplan syndrome. Caplan first described this condition in 1953. He noticed that miners with rheumatoid arthritis had changes on chest radiographs similar to those of progressive massive fibrosis, although the distribution in the lungs was different. Unlike lesions caused by progressive massive fibrosis, which congregate in the upper lobes, these new lesions (subsequently known as Caplan lesions) tend to coalesce in the peripheral lung fields.
|-
! Disease
! Dust
|-
| Coal workers’ pneumoconiosis
| Coal dust
|-
| Silicosis
| Silica
|-
| Asbestosis
| Asbestos
|-
| Talcosis
| Hydrated aluminium silicate
|-
| Kaolin- induced pneumoconiosis
| Hydrous aluminum silicate
|-
| Mixed dust pneumoconiosis
| Coal dust, smoke from fires, and silicates
|-
| Aluminum- induced pneumoconiosis
| Bauxite (Al2O3)
|-
| Berylliosis
| Beryllium
|-
| Silicosiderosis
| Silica and iron
|-
| Hard- metal disease (giant cell pneumonitis)
| Cobalt
|}
 
When particles reach the distal lung, the mucocilliary and lympathic system take care of their elimination. Dust fibers must be less than 3 μm in diameter in order to penetrate the distal lung. Fibers greater than 5 μm are phagocytosed incompletely and retained in tissues. When particles increase in number, macrophages are activated to engulf those particles. Reticulin is then secreted by fibroblasts to entrap macrophages, as an attempt to control the excess of dust particles.
 
The physiology of macrophage activation is subject to several theories. The macrophages are mainly derived from peripheral blood monocytes and, from local replication. The recruitment of monocytes from peripheral blood occurs in response to several chemotactic factorssuggest that one of the most potent chemotactic factors for peripheral blood monocytes is monocyte chemoattractant protein- 1 (MCP- 1), suggesting its role in chronic macrophage inflammation. TNFα activates MCP- 1 expression. MCP-1 is a 76 amino acid peptide that activates monocytes, and also increases its cytostatic activity, and the expression of monocyte adhesion molecules such as CD11c/CD18 and CD11b/CD18.
 
As exposure continues, the elimination system begins to fail, leading to release of reactive oxygen species. These in turn exacerbates the inflammatory response, with the release of more cytokines, such as TNF and interleukins, which subsequently lead to fibrogenesis.
 
The determinants for the rate of disease progression are the accumulative dose; that is based in duration and intensity of exposure, the fiber type and individual susceptibility.
 
The underlying pathogenic mechanisms that lead to pulmonary fibrosis in pneumoconiosis remain suggest a potential protective effect of TGF- β on the development of pulmonary fibrosis. The alveolar macrophages in coal miners with massive fibrosis, secreted two main profibrotic factors; platelet-derived growth factor (PDGF) and insulin-like growth factor- 1 (IGF-1), whereas, the patients with simple pneumoconiosis secreted transforming- growth factor- β (TGF- β). This suggested a potential protective effect of TGF- β against the development of pulmonary fibrosis.
 
The risk for pneumoconiosis among constructions workers is evident, but Tjoe et al concluded there is not a clear-cut relationship between exposure and body’s response. This is hard due to the heterogeneity in exposure levels, as well as dust composition and the possible modification of toxicity by other factors present in dust.<ref>Tjoe E, Borm P, Hohr D and Heederik D (2002)."Pneumoconiosis and Exposure to Quartz-containing Dust in the Construction Industry". British Occupational Hygiene Society. Vol. 46, Supplement 1, pp. 71–75. </ref>
 
==Associated Conditions==
 
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
 
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].


Pathologically, the nodule exhibits a central area of coal dust and necrotic collagenous tissue lying in concentric rings. Surrounding these rings is an area of neutrophils with palisading fibroblasts. Caplan nodules tend to progress faster than lesions associated with progressive massive fibrosis and may precede the onset of rheumatoid lesions. Sixty-two percent of miners with peripheral nodules have positive serology findings for rheumatoid factor. [5]


Research is currently underway to further understand the inciting factors in the inflammatory process. Boitelle et al [6] have suggested that chemokines released to attract alveolar macrophages may be a plausible target for further pharmaceutical intervention to arrest the inflammatory process, which leads to destruction and fibrosis. Levels of monocyte chemoattractant protein-1 have been found to be increased in bronchoalveolar lavage specimens taken from patients with simple coal worker’s pneumoconiosis or progressive massive fibrosis compared with controls. This chemokine, which attracts and activates monocytes, is responsible for the domino effect of respiratory burst, further cell recruitment, and release of lysosomal enzymes. This chemokine may be a key factor in the chronic inflammation of the macrophage, which is central to the pathophysiology of coal worker’s pneumoconiosis. [6]


Other interesting areas that may become promising are the antioxidants selenium and glutathione peroxidase. Both substances have been found to be at lower concentrations in patients who have been exposed to coal-mine dust and tobacco smoke compared with control subjects. This suggests a consumptive process and a weakened defense against reactive oxygen species, which cause cellular damage and potentiate coal worker’s pneumoconiosis and progressive massive fibrosis. [7]


In a 2005 study by Huang et al, [8] a correlation has been found between bioavailable iron (BAI), pyrite concentration, and the regional progression of lung disease. BAI is iron that dissolves in 10 mmol/L phosphate solution at pH 4.5, which mimics the interior of lysosomes. Huang et al [8] found an increased prevalence of coal worker’s pneumoconiosis and progressive massive fibrosis at Pennsylvania mines, where BAI values are higher, compared with Utah mines, where BAI levels are lower. They also demonstrated that pyrite-containing coal contributed to the higher prevalence of progression to coal worker’s pneumoconiosis and progressive massive fibrosis in Pennsylvania. McCunney et al have suggested that iron, not quartz, is the active agent in coal responsible for coal worker’s pneumoconiosis. [9]


When mixed with water, pyrite produces hydrogen peroxide [10, 11] and hydroxyl radicals. [12, 13] These reactive agents have been shown to degrade yeast RNA, ribosomal RNA, and DNA. [11] Cohn et al [14] demonstrated that these pyrite-induced reactive oxygen species can be implicated as the cause of the cellular damage and chronic inflammation that lead to chronic disease in the lungs of coal miners. In order to proceed to RNA degradation, the concentration of sulfur (pyrite) in the coal necessary to produce hydrogen peroxide and hydroxyl radicals must exceed 1%. [14] These findings suggest that personnel at individual mines can measure the amount of sulfur in its coal and implement proper measures to ensure that miners in these high-risk areas either have improved protective gear or decreased long-term exposure to coals with increased BAI.


A case control study by Wang et al in China found that polymorphism in the E-selectin (an adhesion molecule participating in multiple inflammatory processes) gene (SELE) and smoking increased vulnerability to coal worker's pneumoconiosis. [15]


==References==
==References==
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{{Reflist|2}}


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[[Category:Pulmonology]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Overview

Occupational lung diseases include the pneumoconioses (interstitial lung diseases), hypersensitivity pneumonitis, bronchiolitis, byssinosis, and occupational asthma. Pneumoconiosis is an interstitial lung disease caused by the accumulation of different dust particles in the alveolar space. As the particles accumulate, the body's elimination mechanisms begin to fail, resulting in activation of chemotactic factors that exacerbate the inflammatory response, and subsequently lead to fibrosis. Hypersensitivity pneumonitis, bronchiolitis, bysinnosis and occupational asthma are all part of the respiratory systems’ over reactivity to inhalants.

Pathophysiology

Pathogenesis

Pathophysiology

The pathogenesis of pneumoconiosis starts with the inhalation of mineral, metallic or dust particles. . [1][1]. [2] unclear [3]

The most common particles that cause pneumoconiosis are:

  • Asbestos
  • Silica (quartz, cristobalite, coesite or tridymite silica polymorphs)
    • Structural differences between the polymorphs of silica, are important because of the different degrees of biological reactivity they present, making some of them more toxic than others. The biological reactivity makes quartz more toxic, followed by tridymite, cristobalite, coesite, and finally stishovite.
  • Other dust particles may also lead to pneumoconiosis, such as hydrated magnesium silicate, hydrous aluminum silicate, bauxite, cobalt, beryllium and iron.

Biological Reactivity of Different Dust Particles

Each dust particle has a different degree of biological reactivity. This variability is due to properties in the surface of the particles. In the case of silica, there are two theories explaining their biological reactivity. One of them is that silica is a hydrogen donor, whereas biological macromolecules are hydrogen acceptors, creating strong hydrogen bonds that contribute to the damage. The other theory is that at a pH of 7.0, silica is negatively charged, and therefore attracting alveolar macrophages, and activating the generation of reactive oxygen species and cytokines.

Shown below is a table summarizing the dust exposure associated with pneumocociosis.

Disease Dust
Coal workers’ pneumoconiosis Coal dust
Silicosis Silica
Asbestosis Asbestos
Talcosis Hydrated aluminium silicate
Kaolin- induced pneumoconiosis Hydrous aluminum silicate
Mixed dust pneumoconiosis Coal dust, smoke from fires, and silicates
Aluminum- induced pneumoconiosis Bauxite (Al2O3)
Berylliosis Beryllium
Silicosiderosis Silica and iron
Hard- metal disease (giant cell pneumonitis) Cobalt

When particles reach the distal lung, the mucocilliary and lympathic system take care of their elimination. Dust fibers must be less than 3 μm in diameter in order to penetrate the distal lung. Fibers greater than 5 μm are phagocytosed incompletely and retained in tissues. When particles increase in number, macrophages are activated to engulf those particles. Reticulin is then secreted by fibroblasts to entrap macrophages, as an attempt to control the excess of dust particles.

The physiology of macrophage activation is subject to several theories. The macrophages are mainly derived from peripheral blood monocytes and, from local replication. The recruitment of monocytes from peripheral blood occurs in response to several chemotactic factorssuggest that one of the most potent chemotactic factors for peripheral blood monocytes is monocyte chemoattractant protein- 1 (MCP- 1), suggesting its role in chronic macrophage inflammation. TNFα activates MCP- 1 expression. MCP-1 is a 76 amino acid peptide that activates monocytes, and also increases its cytostatic activity, and the expression of monocyte adhesion molecules such as CD11c/CD18 and CD11b/CD18.

As exposure continues, the elimination system begins to fail, leading to release of reactive oxygen species. These in turn exacerbates the inflammatory response, with the release of more cytokines, such as TNF and interleukins, which subsequently lead to fibrogenesis.

The determinants for the rate of disease progression are the accumulative dose; that is based in duration and intensity of exposure, the fiber type and individual susceptibility.

The underlying pathogenic mechanisms that lead to pulmonary fibrosis in pneumoconiosis remain suggest a potential protective effect of TGF- β on the development of pulmonary fibrosis. The alveolar macrophages in coal miners with massive fibrosis, secreted two main profibrotic factors; platelet-derived growth factor (PDGF) and insulin-like growth factor- 1 (IGF-1), whereas, the patients with simple pneumoconiosis secreted transforming- growth factor- β (TGF- β). This suggested a potential protective effect of TGF- β against the development of pulmonary fibrosis.

The risk for pneumoconiosis among constructions workers is evident, but Tjoe et al concluded there is not a clear-cut relationship between exposure and body’s response. This is hard due to the heterogeneity in exposure levels, as well as dust composition and the possible modification of toxicity by other factors present in dust.[4]

Associated Conditions

Gross Pathology

  • On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

  • On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].




References

  1. ↑ 1.0 1.1 Castranova V, Vallyathan V (2000). "Silicosis and coal workers' pneumoconiosis". Environ Health Perspect. 108 Suppl 4: 675–84. PMC 1637684. PMID 10931786.
  2. ↑ name="pmid9072984">Boitelle A, Gosset P, Copin MC, Vanhee D, Marquette CH, Wallaert B; et al. (1997). "MCP-1 secretion in lung from nonsmoking patients with coal worker's pneumoconiosis". Eur Respir J. 10 (3): 557–62. PMID 9072984.
  3. ↑ Vanhée D, Gosset P, Boitelle A, Wallaert B, Tonnel AB (1995). "Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis". Eur Respir J. 8 (5): 834–42. PMID 7656959.
  4. ↑ Tjoe E, Borm P, Hohr D and Heederik D (2002)."Pneumoconiosis and Exposure to Quartz-containing Dust in the Construction Industry". British Occupational Hygiene Society. Vol. 46, Supplement 1, pp. 71–75.
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